BRCA1 Protein: The phosphoprotein encoded by the BRCA1 gene (GENE, BRCA1). In normal cells the BRCA1 protein is localized in the nucleus, whereas in the majority of breast cancer cell lines and in malignant pleural effusions from breast cancer patients, it is localized mainly in the cytoplasm. (Science 1995;270(5237):713,789-91)Genes, BRCA1: A tumor suppressor gene (GENES, TUMOR SUPPRESSOR) located on human CHROMOSOME 17 at locus 17q21. Mutations of this gene are associated with the formation of HEREDITARY BREAST AND OVARIAN CANCER SYNDROME. It encodes a large nuclear protein that is a component of DNA repair pathways.BRCA2 Protein: A large, nuclear protein, encoded by the BRCA2 gene (GENE, BRCA2). Mutations in this gene predispose humans to breast and ovarian cancer. The BRCA2 protein is an essential component of DNA repair pathways, suppressing the formation of gross chromosomal rearrangements. (from Genes Dev. 2000;14(11):1400-6)Genes, BRCA2: A tumor suppressor gene (GENES, TUMOR SUPPRESSOR) located on human chromosome 13 at locus 13q12.3. Mutations in this gene predispose humans to breast and ovarian cancer. It encodes a large, nuclear protein that is an essential component of DNA repair pathways, suppressing the formation of gross chromosomal rearrangements. (from Genes Dev 2000;14(11):1400-6)Mutation: Any detectable and heritable change in the genetic material that causes a change in the GENOTYPE and which is transmitted to daughter cells and to succeeding generations.Point Mutation: A mutation caused by the substitution of one nucleotide for another. This results in the DNA molecule having a change in a single base pair.Germ-Line Mutation: Any detectable and heritable alteration in the lineage of germ cells. Mutations in these cells (i.e., "generative" cells ancestral to the gametes) are transmitted to progeny while those in somatic cells are not.Mutation, Missense: A mutation in which a codon is mutated to one directing the incorporation of a different amino acid. This substitution may result in an inactive or unstable product. (From A Dictionary of Genetics, King & Stansfield, 5th ed)Heterozygote: An individual having different alleles at one or more loci regarding a specific character.Breast Neoplasms: Tumors or cancer of the human BREAST.Ovarian Neoplasms: Tumors or cancer of the OVARY. These neoplasms can be benign or malignant. They are classified according to the tissue of origin, such as the surface EPITHELIUM, the stromal endocrine cells, and the totipotent GERM CELLS.Genetic Testing: Detection of a MUTATION; GENOTYPE; KARYOTYPE; or specific ALLELES associated with genetic traits, heritable diseases, or predisposition to a disease, or that may lead to the disease in descendants. It includes prenatal genetic testing.Frameshift Mutation: A type of mutation in which a number of NUCLEOTIDES deleted from or inserted into a protein coding sequence is not divisible by three, thereby causing an alteration in the READING FRAMES of the entire coding sequence downstream of the mutation. These mutations may be induced by certain types of MUTAGENS or may occur spontaneously.DNA Mutational Analysis: Biochemical identification of mutational changes in a nucleotide sequence.Genetic Predisposition to Disease: A latent susceptibility to disease at the genetic level, which may be activated under certain conditions.Pedigree: The record of descent or ancestry, particularly of a particular condition or trait, indicating individual family members, their relationships, and their status with respect to the trait or condition.Base Sequence: The sequence of PURINES and PYRIMIDINES in nucleic acids and polynucleotides. It is also called nucleotide sequence.Transcription Factors: Endogenous substances, usually proteins, which are effective in the initiation, stimulation, or termination of the genetic transcription process.Neoplasm Proteins: Proteins whose abnormal expression (gain or loss) are associated with the development, growth, or progression of NEOPLASMS. Some neoplasm proteins are tumor antigens (ANTIGENS, NEOPLASM), i.e. they induce an immune reaction to their tumor. Many neoplasm proteins have been characterized and are used as tumor markers (BIOMARKERS, TUMOR) when they are detectable in cells and body fluids as monitors for the presence or growth of tumors. Abnormal expression of ONCOGENE PROTEINS is involved in neoplastic transformation, whereas the loss of expression of TUMOR SUPPRESSOR PROTEINS is involved with the loss of growth control and progression of the neoplasm.Rad51 Recombinase: A Rec A recombinase found in eukaryotes. Rad51 is involved in DNA REPAIR of double-strand breaks.Molecular Sequence Data: Descriptions of specific amino acid, carbohydrate, or nucleotide sequences which have appeared in the published literature and/or are deposited in and maintained by databanks such as GENBANK, European Molecular Biology Laboratory (EMBL), National Biomedical Research Foundation (NBRF), or other sequence repositories.Exons: The parts of a transcript of a split GENE remaining after the INTRONS are removed. They are spliced together to become a MESSENGER RNA or other functional RNA.Polymorphism, Single-Stranded Conformational: Variation in a population's DNA sequence that is detected by determining alterations in the conformation of denatured DNA fragments. Denatured DNA fragments are allowed to renature under conditions that prevent the formation of double-stranded DNA and allow secondary structure to form in single stranded fragments. These fragments are then run through polyacrylamide gels to detect variations in the secondary structure that is manifested as an alteration in migration through the gels.DNA Repair: The reconstruction of a continuous two-stranded DNA molecule without mismatch from a molecule which contained damaged regions. The major repair mechanisms are excision repair, in which defective regions in one strand are excised and resynthesized using the complementary base pairing information in the intact strand; photoreactivation repair, in which the lethal and mutagenic effects of ultraviolet light are eliminated; and post-replication repair, in which the primary lesions are not repaired, but the gaps in one daughter duplex are filled in by incorporation of portions of the other (undamaged) daughter duplex. Excision repair and post-replication repair are sometimes referred to as "dark repair" because they do not require light.Polymerase Chain Reaction: In vitro method for producing large amounts of specific DNA or RNA fragments of defined length and sequence from small amounts of short oligonucleotide flanking sequences (primers). The essential steps include thermal denaturation of the double-stranded target molecules, annealing of the primers to their complementary sequences, and extension of the annealed primers by enzymatic synthesis with DNA polymerase. The reaction is efficient, specific, and extremely sensitive. Uses for the reaction include disease diagnosis, detection of difficult-to-isolate pathogens, mutation analysis, genetic testing, DNA sequencing, and analyzing evolutionary relationships.DNA Damage: Injuries to DNA that introduce deviations from its normal, intact structure and which may, if left unrepaired, result in a MUTATION or a block of DNA REPLICATION. These deviations may be caused by physical or chemical agents and occur by natural or unnatural, introduced circumstances. They include the introduction of illegitimate bases during replication or by deamination or other modification of bases; the loss of a base from the DNA backbone leaving an abasic site; single-strand breaks; double strand breaks; and intrastrand (PYRIMIDINE DIMERS) or interstrand crosslinking. Damage can often be repaired (DNA REPAIR). If the damage is extensive, it can induce APOPTOSIS.Cell Line: Established cell cultures that have the potential to propagate indefinitely.DNA-Binding Proteins: Proteins which bind to DNA. The family includes proteins which bind to both double- and single-stranded DNA and also includes specific DNA binding proteins in serum which can be used as markers for malignant diseases.Phenotype: The outward appearance of the individual. It is the product of interactions between genes, and between the GENOTYPE and the environment.Genes, p53: Tumor suppressor genes located on the short arm of human chromosome 17 and coding for the phosphoprotein p53.Amino Acid Sequence: The order of amino acids as they occur in a polypeptide chain. This is referred to as the primary structure of proteins. It is of fundamental importance in determining PROTEIN CONFORMATION.Transcription, Genetic: The biosynthesis of RNA carried out on a template of DNA. The biosynthesis of DNA from an RNA template is called REVERSE TRANSCRIPTION.Mutation Rate: The number of mutations that occur in a specific sequence, GENE, or GENOME over a specified period of time such as years, CELL DIVISIONS, or generations.Genotype: The genetic constitution of the individual, comprising the ALLELES present at each GENETIC LOCUS.Alleles: Variant forms of the same gene, occupying the same locus on homologous CHROMOSOMES, and governing the variants in production of the same gene product.Tumor Cells, Cultured: Cells grown in vitro from neoplastic tissue. If they can be established as a TUMOR CELL LINE, they can be propagated in cell culture indefinitely.Gene Expression Regulation, Viral: Any of the processes by which cytoplasmic factors influence the differential control of gene action in viruses.Promoter Regions, Genetic: DNA sequences which are recognized (directly or indirectly) and bound by a DNA-dependent RNA polymerase during the initiation of transcription. Highly conserved sequences within the promoter include the Pribnow box in bacteria and the TATA BOX in eukaryotes.Amino Acid Substitution: The naturally occurring or experimentally induced replacement of one or more AMINO ACIDS in a protein with another. If a functionally equivalent amino acid is substituted, the protein may retain wild-type activity. Substitution may also diminish, enhance, or eliminate protein function. Experimentally induced substitution is often used to study enzyme activities and binding site properties.Sequence Analysis, DNA: A multistage process that includes cloning, physical mapping, subcloning, determination of the DNA SEQUENCE, and information analysis.Codon, Nonsense: An amino acid-specifying codon that has been converted to a stop codon (CODON, TERMINATOR) by mutation. Its occurance is abnormal causing premature termination of protein translation and results in production of truncated and non-functional proteins. A nonsense mutation is one that converts an amino acid-specific codon to a stop codon.Homozygote: An individual in which both alleles at a given locus are identical.Nuclear Proteins: Proteins found in the nucleus of a cell. Do not confuse with NUCLEOPROTEINS which are proteins conjugated with nucleic acids, that are not necessarily present in the nucleus.Founder Effect: A phenomenon that is observed when a small subgroup of a larger POPULATION establishes itself as a separate and isolated entity. The subgroup's GENE POOL carries only a fraction of the genetic diversity of the parental population resulting in an increased frequency of certain diseases in the subgroup, especially those diseases known to be autosomal recessive.Gene Expression Regulation: Any of the processes by which nuclear, cytoplasmic, or intercellular factors influence the differential control (induction or repression) of gene action at the level of transcription or translation.Sequence Deletion: Deletion of sequences of nucleic acids from the genetic material of an individual.Jews: An ethnic group with historical ties to the land of ISRAEL and the religion of JUDAISM.DNA, Neoplasm: DNA present in neoplastic tissue.DNA Primers: Short sequences (generally about 10 base pairs) of DNA that are complementary to sequences of messenger RNA and allow reverse transcriptases to start copying the adjacent sequences of mRNA. Primers are used extensively in genetic and molecular biology techniques.Transfection: The uptake of naked or purified DNA by CELLS, usually meaning the process as it occurs in eukaryotic cells. It is analogous to bacterial transformation (TRANSFORMATION, BACTERIAL) and both are routinely employed in GENE TRANSFER TECHNIQUES.RNA, Messenger: RNA sequences that serve as templates for protein synthesis. Bacterial mRNAs are generally primary transcripts in that they do not require post-transcriptional processing. Eukaryotic mRNA is synthesized in the nucleus and must be exported to the cytoplasm for translation. Most eukaryotic mRNAs have a sequence of polyadenylic acid at the 3' end, referred to as the poly(A) tail. The function of this tail is not known for certain, but it may play a role in the export of mature mRNA from the nucleus as well as in helping stabilize some mRNA molecules by retarding their degradation in the cytoplasm.DNA: A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine).Mutagenesis: Process of generating a genetic MUTATION. It may occur spontaneously or be induced by MUTAGENS.Mutagenesis, Site-Directed: Genetically engineered MUTAGENESIS at a specific site in the DNA molecule that introduces a base substitution, or an insertion or deletion.Gene Deletion: A genetic rearrangement through loss of segments of DNA or RNA, bringing sequences which are normally separated into close proximity. This deletion may be detected using cytogenetic techniques and can also be inferred from the phenotype, indicating a deletion at one specific locus.Tumor Suppressor Protein p53: Nuclear phosphoprotein encoded by the p53 gene (GENES, P53) whose normal function is to control CELL PROLIFERATION and APOPTOSIS. A mutant or absent p53 protein has been found in LEUKEMIA; OSTEOSARCOMA; LUNG CANCER; and COLORECTAL CANCER.Transcriptional Activation: Processes that stimulate the GENETIC TRANSCRIPTION of a gene or set of genes.Binding Sites: The parts of a macromolecule that directly participate in its specific combination with another molecule.Genes, Recessive: Genes that influence the PHENOTYPE only in the homozygous state.Protein Structure, Tertiary: The level of protein structure in which combinations of secondary protein structures (alpha helices, beta sheets, loop regions, and motifs) pack together to form folded shapes called domains. Disulfide bridges between cysteines in two different parts of the polypeptide chain along with other interactions between the chains play a role in the formation and stabilization of tertiary structure. Small proteins usually consist of only one domain but larger proteins may contain a number of domains connected by segments of polypeptide chain which lack regular secondary structure.HeLa Cells: The first continuously cultured human malignant CELL LINE, derived from the cervical carcinoma of Henrietta Lacks. These cells are used for VIRUS CULTIVATION and antitumor drug screening assays.Family Health: The health status of the family as a unit including the impact of the health of one member of the family on the family as a unit and on individual family members; also, the impact of family organization or disorganization on the health status of its members.Heterozygote Detection: Identification of genetic carriers for a given trait.Cloning, Molecular: The insertion of recombinant DNA molecules from prokaryotic and/or eukaryotic sources into a replicating vehicle, such as a plasmid or virus vector, and the introduction of the resultant hybrid molecules into recipient cells without altering the viability of those cells.Codon: A set of three nucleotides in a protein coding sequence that specifies individual amino acids or a termination signal (CODON, TERMINATOR). Most codons are universal, but some organisms do not produce the transfer RNAs (RNA, TRANSFER) complementary to all codons. These codons are referred to as unassigned codons (CODONS, NONSENSE).Plasmids: Extrachromosomal, usually CIRCULAR DNA molecules that are self-replicating and transferable from one organism to another. They are found in a variety of bacterial, archaeal, fungal, algal, and plant species. They are used in GENETIC ENGINEERING as CLONING VECTORS.Brain Stem: The part of the brain that connects the CEREBRAL HEMISPHERES with the SPINAL CORD. It consists of the MESENCEPHALON; PONS; and MEDULLA OBLONGATA.Protein Binding: The process in which substances, either endogenous or exogenous, bind to proteins, peptides, enzymes, protein precursors, or allied compounds. Specific protein-binding measures are often used as assays in diagnostic assessments.Genes, Dominant: Genes that influence the PHENOTYPE both in the homozygous and the heterozygous state.Chromosome Mapping: Any method used for determining the location of and relative distances between genes on a chromosome.Gene Products, tax: Transcriptional trans-acting proteins of the promoter elements found in the long terminal repeats (LTR) of HUMAN T-LYMPHOTROPIC VIRUS 1 and HUMAN T-LYMPHOTROPIC VIRUS 2. The tax (trans-activator x; x is undefined) proteins act by binding to enhancer elements in the LTR.Viral Proteins: Proteins found in any species of virus.Carrier Proteins: Transport proteins that carry specific substances in the blood or across cell membranes.Cell Transformation, Viral: An inheritable change in cells manifested by changes in cell division and growth and alterations in cell surface properties. It is induced by infection with a transforming virus.Oncogenes: Genes whose gain-of-function alterations lead to NEOPLASTIC CELL TRANSFORMATION. They include, for example, genes for activators or stimulators of CELL PROLIFERATION such as growth factors, growth factor receptors, protein kinases, signal transducers, nuclear phosphoproteins, and transcription factors. A prefix of "v-" before oncogene symbols indicates oncogenes captured and transmitted by RETROVIRUSES; the prefix "c-" before the gene symbol of an oncogene indicates it is the cellular homolog (PROTO-ONCOGENES) of a v-oncogene.Membrane Proteins: Proteins which are found in membranes including cellular and intracellular membranes. They consist of two types, peripheral and integral proteins. They include most membrane-associated enzymes, antigenic proteins, transport proteins, and drug, hormone, and lectin receptors.Gene Expression Profiling: The determination of the pattern of genes expressed at the level of GENETIC TRANSCRIPTION, under specific circumstances or in a specific cell.Syndrome: A characteristic symptom complex.Polymorphism, Genetic: The regular and simultaneous occurrence in a single interbreeding population of two or more discontinuous genotypes. The concept includes differences in genotypes ranging in size from a single nucleotide site (POLYMORPHISM, SINGLE NUCLEOTIDE) to large nucleotide sequences visible at a chromosomal level.Genes: A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms.Gene Frequency: The proportion of one particular in the total of all ALLELES for one genetic locus in a breeding POPULATION.Cell Transformation, Neoplastic: Cell changes manifested by escape from control mechanisms, increased growth potential, alterations in the cell surface, karyotypic abnormalities, morphological and biochemical deviations from the norm, and other attributes conferring the ability to invade, metastasize, and kill.Sequence Homology, Amino Acid: The degree of similarity between sequences of amino acids. This information is useful for the analyzing genetic relatedness of proteins and species.Sequence Alignment: The arrangement of two or more amino acid or base sequences from an organism or organisms in such a way as to align areas of the sequences sharing common properties. The degree of relatedness or homology between the sequences is predicted computationally or statistically based on weights assigned to the elements aligned between the sequences. This in turn can serve as a potential indicator of the genetic relatedness between the organisms.Models, Genetic: Theoretical representations that simulate the behavior or activity of genetic processes or phenomena. They include the use of mathematical equations, computers, and other electronic equipment.Proto-Oncogene Proteins: Products of proto-oncogenes. Normally they do not have oncogenic or transforming properties, but are involved in the regulation or differentiation of cell growth. They often have protein kinase activity.Cells, Cultured: Cells propagated in vitro in special media conducive to their growth. Cultured cells are used to study developmental, morphologic, metabolic, physiologic, and genetic processes, among others.Reverse Transcriptase Polymerase Chain Reaction: A variation of the PCR technique in which cDNA is made from RNA via reverse transcription. The resultant cDNA is then amplified using standard PCR protocols.Neoplastic Syndromes, Hereditary: The condition of a pattern of malignancies within a family, but not every individual's necessarily having the same neoplasm. Characteristically the tumor tends to occur at an earlier than average age, individuals may have more than one primary tumor, the tumors may be multicentric, usually more than 25 percent of the individuals in direct lineal descent from the proband are affected, and the cancer predisposition in these families behaves as an autosomal dominant trait with about 60 percent penetrance.Oligonucleotide Array Sequence Analysis: Hybridization of a nucleic acid sample to a very large set of OLIGONUCLEOTIDE PROBES, which have been attached individually in columns and rows to a solid support, to determine a BASE SEQUENCE, or to detect variations in a gene sequence, GENE EXPRESSION, or for GENE MAPPING.Virus Replication: The process of intracellular viral multiplication, consisting of the synthesis of PROTEINS; NUCLEIC ACIDS; and sometimes LIPIDS, and their assembly into a new infectious particle.Genes, Viral: The functional hereditary units of VIRUSES.Gene Expression Regulation, Neoplastic: Any of the processes by which nuclear, cytoplasmic, or intercellular factors influence the differential control of gene action in neoplastic tissue.Introns: Sequences of DNA in the genes that are located between the EXONS. They are transcribed along with the exons but are removed from the primary gene transcript by RNA SPLICING to leave mature RNA. Some introns code for separate genes.Penetrance: The percent frequency with which a dominant or homozygous recessive gene or gene combination manifests itself in the phenotype of the carriers. (From Glossary of Genetics, 5th ed)Gene Expression: The phenotypic manifestation of a gene or genes by the processes of GENETIC TRANSCRIPTION and GENETIC TRANSLATION.Human T-lymphotropic virus 1: A strain of PRIMATE T-LYMPHOTROPIC VIRUS 1 isolated from mature T4 cells in patients with T-lymphoproliferation malignancies. It causes adult T-cell leukemia (LEUKEMIA-LYMPHOMA, T-CELL, ACUTE, HTLV-I-ASSOCIATED), T-cell lymphoma (LYMPHOMA, T-CELL), and is involved in mycosis fungoides, SEZARY SYNDROME and tropical spastic paraparesis (PARAPARESIS, TROPICAL SPASTIC).Loss of Heterozygosity: The loss of one allele at a specific locus, caused by a deletion mutation; or loss of a chromosome from a chromosome pair, resulting in abnormal HEMIZYGOSITY. It is detected when heterozygous markers for a locus appear monomorphic because one of the ALLELES was deleted.Consanguinity: The magnitude of INBREEDING in humans.Genetic Counseling: An educational process that provides information and advice to individuals or families about a genetic condition that may affect them. The purpose is to help individuals make informed decisions about marriage, reproduction, and other health management issues based on information about the genetic disease, the available diagnostic tests, and management programs. Psychosocial support is usually offered.Genetic Linkage: The co-inheritance of two or more non-allelic GENES due to their being located more or less closely on the same CHROMOSOME.Genes, ras: Family of retrovirus-associated DNA sequences (ras) originally isolated from Harvey (H-ras, Ha-ras, rasH) and Kirsten (K-ras, Ki-ras, rasK) murine sarcoma viruses. Ras genes are widely conserved among animal species and sequences corresponding to both H-ras and K-ras genes have been detected in human, avian, murine, and non-vertebrate genomes. The closely related N-ras gene has been detected in human neuroblastoma and sarcoma cell lines. All genes of the family have a similar exon-intron structure and each encodes a p21 protein.Signal Transduction: The intracellular transfer of information (biological activation/inhibition) through a signal pathway. In each signal transduction system, an activation/inhibition signal from a biologically active molecule (hormone, neurotransmitter) is mediated via the coupling of a receptor/enzyme to a second messenger system or to an ion channel. Signal transduction plays an important role in activating cellular functions, cell differentiation, and cell proliferation. Examples of signal transduction systems are the GAMMA-AMINOBUTYRIC ACID-postsynaptic receptor-calcium ion channel system, the receptor-mediated T-cell activation pathway, and the receptor-mediated activation of phospholipases. Those coupled to membrane depolarization or intracellular release of calcium include the receptor-mediated activation of cytotoxic functions in granulocytes and the synaptic potentiation of protein kinase activation. Some signal transduction pathways may be part of larger signal transduction pathways; for example, protein kinase activation is part of the platelet activation signal pathway.Models, Molecular: Models used experimentally or theoretically to study molecular shape, electronic properties, or interactions; includes analogous molecules, computer-generated graphics, and mechanical structures.Mutagenesis, Insertional: Mutagenesis where the mutation is caused by the introduction of foreign DNA sequences into a gene or extragenic sequence. This may occur spontaneously in vivo or be experimentally induced in vivo or in vitro. Proviral DNA insertions into or adjacent to a cellular proto-oncogene can interrupt GENETIC TRANSLATION of the coding sequences or interfere with recognition of regulatory elements and cause unregulated expression of the proto-oncogene resulting in tumor formation.Ubiquitin-Protein Ligases: A diverse class of enzymes that interact with UBIQUITIN-CONJUGATING ENZYMES and ubiquitination-specific protein substrates. Each member of this enzyme group has its own distinct specificity for a substrate and ubiquitin-conjugating enzyme. Ubiquitin-protein ligases exist as both monomeric proteins multiprotein complexes.Recombination, Genetic: Production of new arrangements of DNA by various mechanisms such as assortment and segregation, CROSSING OVER; GENE CONVERSION; GENETIC TRANSFORMATION; GENETIC CONJUGATION; GENETIC TRANSDUCTION; or mixed infection of viruses.Cell Line, Tumor: A cell line derived from cultured tumor cells.DNA, Viral: Deoxyribonucleic acid that makes up the genetic material of viruses.Epstein-Barr Virus Nuclear Antigens: Nuclear antigens encoded by VIRAL GENES found in HUMAN HERPESVIRUS 4. At least six nuclear antigens have been identified.Tumor Suppressor Proteins: Proteins that are normally involved in holding cellular growth in check. Deficiencies or abnormalities in these proteins may lead to unregulated cell growth and tumor development.Terminal Repeat Sequences: Nucleotide sequences repeated on both the 5' and 3' ends of a sequence under consideration. For example, the hallmarks of a transposon are that it is flanked by inverted repeats on each end and the inverted repeats are flanked by direct repeats. The Delta element of Ty retrotransposons and LTRs (long terminal repeats) are examples of this concept.Escherichia coli: A species of gram-negative, facultatively anaerobic, rod-shaped bacteria (GRAM-NEGATIVE FACULTATIVELY ANAEROBIC RODS) commonly found in the lower part of the intestine of warm-blooded animals. It is usually nonpathogenic, but some strains are known to produce DIARRHEA and pyogenic infections. Pathogenic strains (virotypes) are classified by their specific pathogenic mechanisms such as toxins (ENTEROTOXIGENIC ESCHERICHIA COLI), etc.Repetitive Sequences, Nucleic Acid: Sequences of DNA or RNA that occur in multiple copies. There are several types: INTERSPERSED REPETITIVE SEQUENCES are copies of transposable elements (DNA TRANSPOSABLE ELEMENTS or RETROELEMENTS) dispersed throughout the genome. TERMINAL REPEAT SEQUENCES flank both ends of another sequence, for example, the long terminal repeats (LTRs) on RETROVIRUSES. Variations may be direct repeats, those occurring in the same direction, or inverted repeats, those opposite to each other in direction. TANDEM REPEAT SEQUENCES are copies which lie adjacent to each other, direct or inverted (INVERTED REPEAT SEQUENCES).DNA, Complementary: Single-stranded complementary DNA synthesized from an RNA template by the action of RNA-dependent DNA polymerase. cDNA (i.e., complementary DNA, not circular DNA, not C-DNA) is used in a variety of molecular cloning experiments as well as serving as a specific hybridization probe.Proteins: Linear POLYPEPTIDES that are synthesized on RIBOSOMES and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of AMINO ACIDS determines the shape the polypeptide will take, during PROTEIN FOLDING, and the function of the protein.Microsatellite Repeats: A variety of simple repeat sequences that are distributed throughout the GENOME. They are characterized by a short repeat unit of 2-8 basepairs that is repeated up to 100 times. They are also known as short tandem repeats (STRs).Asian Continental Ancestry Group: Individuals whose ancestral origins are in the southeastern and eastern areas of the Asian continent.Repressor Proteins: Proteins which maintain the transcriptional quiescence of specific GENES or OPERONS. Classical repressor proteins are DNA-binding proteins that are normally bound to the OPERATOR REGION of an operon, or the ENHANCER SEQUENCES of a gene until a signal occurs that causes their release.Cell Nucleus: Within a eukaryotic cell, a membrane-limited body which contains chromosomes and one or more nucleoli (CELL NUCLEOLUS). The nuclear membrane consists of a double unit-type membrane which is perforated by a number of pores; the outermost membrane is continuous with the ENDOPLASMIC RETICULUM. A cell may contain more than one nucleus. (From Singleton & Sainsbury, Dictionary of Microbiology and Molecular Biology, 2d ed)Genetic Complementation Test: A test used to determine whether or not complementation (compensation in the form of dominance) will occur in a cell with a given mutant phenotype when another mutant genome, encoding the same mutant phenotype, is introduced into that cell.Fibroblasts: Connective tissue cells which secrete an extracellular matrix rich in collagen and other macromolecules.Proto-Oncogene Proteins B-raf: A raf kinase subclass found at high levels in neuronal tissue. The B-raf Kinases are MAP kinase kinase kinases that have specificity for MAP KINASE KINASE 1 and MAP KINASE KINASE 2.Mutant Proteins: Proteins produced from GENES that have acquired MUTATIONS.Suppression, Genetic: Mutation process that restores the wild-type PHENOTYPE in an organism possessing a mutationally altered GENOTYPE. The second "suppressor" mutation may be on a different gene, on the same gene but located at a distance from the site of the primary mutation, or in extrachromosomal genes (EXTRACHROMOSOMAL INHERITANCE).Genetic Diseases, X-Linked: Genetic diseases that are linked to gene mutations on the X CHROMOSOME in humans (X CHROMOSOME, HUMAN) or the X CHROMOSOME in other species. Included here are animal models of human X-linked diseases.Adenovirus Early Proteins: Proteins encoded by adenoviruses that are synthesized prior to, and in the absence of, viral DNA replication. The proteins are involved in both positive and negative regulation of expression in viral and cellular genes, and also affect the stability of viral mRNA. Some are also involved in oncogenic transformation.Recombinant Fusion Proteins: Recombinant proteins produced by the GENETIC TRANSLATION of fused genes formed by the combination of NUCLEIC ACID REGULATORY SEQUENCES of one or more genes with the protein coding sequences of one or more genes.Genetic Variation: Genotypic differences observed among individuals in a population.Cercopithecus aethiops: A species of CERCOPITHECUS containing three subspecies: C. tantalus, C. pygerythrus, and C. sabeus. They are found in the forests and savannah of Africa. The African green monkey (C. pygerythrus) is the natural host of SIMIAN IMMUNODEFICIENCY VIRUS and is used in AIDS research.Polymorphism, Restriction Fragment Length: Variation occurring within a species in the presence or length of DNA fragment generated by a specific endonuclease at a specific site in the genome. Such variations are generated by mutations that create or abolish recognition sites for these enzymes or change the length of the fragment.Immunohistochemistry: Histochemical localization of immunoreactive substances using labeled antibodies as reagents.Exome: That part of the genome that corresponds to the complete complement of EXONS of an organism or cell.RNA Splicing: The ultimate exclusion of nonsense sequences or intervening sequences (introns) before the final RNA transcript is sent to the cytoplasm.Genes, APC: Tumor suppressor genes located in the 5q21 region on the long arm of human chromosome 5. The mutation of these genes is associated with familial adenomatous polyposis (ADENOMATOUS POLYPOSIS COLI) and GARDNER SYNDROME, as well as some sporadic colorectal cancers.Immediate-Early Proteins: Proteins that are coded by immediate-early genes, in the absence of de novo protein synthesis. The term was originally used exclusively for viral regulatory proteins that were synthesized just after viral integration into the host cell. It is also used to describe cellular proteins which are synthesized immediately after the resting cell is stimulated by extracellular signals.Cell Line, Transformed: Eukaryotic cell line obtained in a quiescent or stationary phase which undergoes conversion to a state of unregulated growth in culture, resembling an in vitro tumor. It occurs spontaneously or through interaction with viruses, oncogenes, radiation, or drugs/chemicals.Recombinant Proteins: Proteins prepared by recombinant DNA technology.COS Cells: CELL LINES derived from the CV-1 cell line by transformation with a replication origin defective mutant of SV40 VIRUS, which codes for wild type large T antigen (ANTIGENS, POLYOMAVIRUS TRANSFORMING). They are used for transfection and cloning. (The CV-1 cell line was derived from the kidney of an adult male African green monkey (CERCOPITHECUS AETHIOPS).)Mutagens: Chemical agents that increase the rate of genetic mutation by interfering with the function of nucleic acids. A clastogen is a specific mutagen that causes breaks in chromosomes.Nucleic Acid Hybridization: Widely used technique which exploits the ability of complementary sequences in single-stranded DNAs or RNAs to pair with each other to form a double helix. Hybridization can take place between two complimentary DNA sequences, between a single-stranded DNA and a complementary RNA, or between two RNA sequences. The technique is used to detect and isolate specific sequences, measure homology, or define other characteristics of one or both strands. (Kendrew, Encyclopedia of Molecular Biology, 1994, p503)Cell Cycle Proteins: Proteins that control the CELL DIVISION CYCLE. This family of proteins includes a wide variety of classes, including CYCLIN-DEPENDENT KINASES, mitogen-activated kinases, CYCLINS, and PHOSPHOPROTEIN PHOSPHATASES as well as their putative substrates such as chromatin-associated proteins, CYTOSKELETAL PROTEINS, and TRANSCRIPTION FACTORS.Breast Neoplasms, Male: Any neoplasms of the male breast. These occur infrequently in males in developed countries, the incidence being about 1% of that in females.DNA, Mitochondrial: Double-stranded DNA of MITOCHONDRIA. In eukaryotes, the mitochondrial GENOME is circular and codes for ribosomal RNAs, transfer RNAs, and about 10 proteins.Case-Control Studies: Studies which start with the identification of persons with a disease of interest and a control (comparison, referent) group without the disease. The relationship of an attribute to the disease is examined by comparing diseased and non-diseased persons with regard to the frequency or levels of the attribute in each group.Adenoviruses, Human: Species of the genus MASTADENOVIRUS, causing a wide range of diseases in humans. Infections are mostly asymptomatic, but can be associated with diseases of the respiratory, ocular, and gastrointestinal systems. Serotypes (named with Arabic numbers) have been grouped into species designated Human adenovirus A-F.RNA, Viral: Ribonucleic acid that makes up the genetic material of viruses.Restriction Mapping: Use of restriction endonucleases to analyze and generate a physical map of genomes, genes, or other segments of DNA.Cricetinae: A subfamily in the family MURIDAE, comprising the hamsters. Four of the more common genera are Cricetus, CRICETULUS; MESOCRICETUS; and PHODOPUS.Herpesvirus 8, Human: A species in the genus RHADINOVIRUS, subfamily GAMMAHERPESVIRINAE, isolated from patients with AIDS-related and "classical" Kaposi sarcoma.Polymorphism, Single Nucleotide: A single nucleotide variation in a genetic sequence that occurs at appreciable frequency in the population.Conserved Sequence: A sequence of amino acids in a polypeptide or of nucleotides in DNA or RNA that is similar across multiple species. A known set of conserved sequences is represented by a CONSENSUS SEQUENCE. AMINO ACID MOTIFS are often composed of conserved sequences.Genetic Markers: A phenotypically recognizable genetic trait which can be used to identify a genetic locus, a linkage group, or a recombination event.Saccharomyces cerevisiae: A species of the genus SACCHAROMYCES, family Saccharomycetaceae, order Saccharomycetales, known as "baker's" or "brewer's" yeast. The dried form is used as a dietary supplement.Protein-Serine-Threonine Kinases: A group of enzymes that catalyzes the phosphorylation of serine or threonine residues in proteins, with ATP or other nucleotides as phosphate donors.Colorectal Neoplasms, Hereditary Nonpolyposis: A group of autosomal-dominant inherited diseases in which COLON CANCER arises in discrete adenomas. Unlike FAMILIAL POLYPOSIS COLI with hundreds of polyps, hereditary nonpolyposis colorectal neoplasms occur much later, in the fourth and fifth decades. HNPCC has been associated with germline mutations in mismatch repair (MMR) genes. It has been subdivided into Lynch syndrome I or site-specific colonic cancer, and LYNCH SYNDROME II which includes extracolonic cancer.Oncogene Proteins, Viral: Products of viral oncogenes, most commonly retroviral oncogenes. They usually have transforming and often protein kinase activities.MutS Homolog 2 Protein: MutS homolog 2 protein is found throughout eukaryotes and is a homolog of the MUTS DNA MISMATCH-BINDING PROTEIN. It plays an essential role in meiotic RECOMBINATION and DNA REPAIR of mismatched NUCLEOTIDES.Blotting, Western: Identification of proteins or peptides that have been electrophoretically separated by blot transferring from the electrophoresis gel to strips of nitrocellulose paper, followed by labeling with antibody probes.Bacterial Proteins: Proteins found in any species of bacterium.Chromosomes, Human, Pair 17: A specific pair of GROUP E CHROMOSOMES of the human chromosome classification.Herpesvirus 4, Human: The type species of LYMPHOCRYPTOVIRUS, subfamily GAMMAHERPESVIRINAE, infecting B-cells in humans. It is thought to be the causative agent of INFECTIOUS MONONUCLEOSIS and is strongly associated with oral hairy leukoplakia (LEUKOPLAKIA, HAIRY;), BURKITT LYMPHOMA; and other malignancies.Phosphorylation: The introduction of a phosphoryl group into a compound through the formation of an ester bond between the compound and a phosphorus moiety.Eye ProteinsFamily: A social group consisting of parents or parent substitutes and children.Host-Pathogen Interactions: The interactions between a host and a pathogen, usually resulting in disease.Genes, Lethal: Genes whose loss of function or gain of function MUTATION leads to the death of the carrier prior to maturity. They may be essential genes (GENES, ESSENTIAL) required for viability, or genes which cause a block of function of an essential gene at a time when the essential gene function is required for viability.DNA Mismatch Repair: A DNA repair pathway involved in correction of errors introduced during DNA replication when an incorrect base, which cannot form hydrogen bonds with the corresponding base in the parent strand, is incorporated into the daughter strand. Excinucleases recognize the BASE PAIR MISMATCH and cause a segment of polynucleotide chain to be excised from the daughter strand, thereby removing the mismatched base. (from Oxford Dictionary of Biochemistry and Molecular Biology, 2001)Proto-Oncogenes: Normal cellular genes homologous to viral oncogenes. The products of proto-oncogenes are important regulators of biological processes and appear to be involved in the events that serve to maintain the ordered procession through the cell cycle. Proto-oncogenes have names of the form c-onc.RNA Splice Sites: Nucleotide sequences located at the ends of EXONS and recognized in pre-messenger RNA by SPLICEOSOMES. They are joined during the RNA SPLICING reaction, forming the junctions between exons.Open Reading Frames: A sequence of successive nucleotide triplets that are read as CODONS specifying AMINO ACIDS and begin with an INITIATOR CODON and end with a stop codon (CODON, TERMINATOR).Cell Cycle: The complex series of phenomena, occurring between the end of one CELL DIVISION and the end of the next, by which cellular material is duplicated and then divided between two daughter cells. The cell cycle includes INTERPHASE, which includes G0 PHASE; G1 PHASE; S PHASE; and G2 PHASE, and CELL DIVISION PHASE.Mice, Transgenic: Laboratory mice that have been produced from a genetically manipulated EGG or EMBRYO, MAMMALIAN.Alternative Splicing: A process whereby multiple RNA transcripts are generated from a single gene. Alternative splicing involves the splicing together of other possible sets of EXONS during the processing of some, but not all, transcripts of the gene. Thus a particular exon may be connected to any one of several alternative exons to form a mature RNA. The alternative forms of mature MESSENGER RNA produce PROTEIN ISOFORMS in which one part of the isoforms is common while the other parts are different.Genetic Association Studies: The analysis of a sequence such as a region of a chromosome, a haplotype, a gene, or an allele for its involvement in controlling the phenotype of a specific trait, metabolic pathway, or disease.Genes, Tumor Suppressor: Genes that inhibit expression of the tumorigenic phenotype. They are normally involved in holding cellular growth in check. When tumor suppressor genes are inactivated or lost, a barrier to normal proliferation is removed and unregulated growth is possible.Genes, Reporter: Genes whose expression is easily detectable and therefore used to study promoter activity at many positions in a target genome. In recombinant DNA technology, these genes may be attached to a promoter region of interest.Structure-Activity Relationship: The relationship between the chemical structure of a compound and its biological or pharmacological activity. Compounds are often classed together because they have structural characteristics in common including shape, size, stereochemical arrangement, and distribution of functional groups.Ethylnitrosourea: A nitrosourea compound with alkylating, carcinogenic, and mutagenic properties.Genetic Vectors: DNA molecules capable of autonomous replication within a host cell and into which other DNA sequences can be inserted and thus amplified. Many are derived from PLASMIDS; BACTERIOPHAGES; or VIRUSES. They are used for transporting foreign genes into recipient cells. Genetic vectors possess a functional replicator site and contain GENETIC MARKERS to facilitate their selective recognition.Kinetics: The rate dynamics in chemical or physical systems.Adenocarcinoma: A malignant epithelial tumor with a glandular organization.Mice, Mutant Strains: Mice bearing mutant genes which are phenotypically expressed in the animals.Blotting, Southern: A method (first developed by E.M. Southern) for detection of DNA that has been electrophoretically separated and immobilized by blotting on nitrocellulose or other type of paper or nylon membrane followed by hybridization with labeled NUCLEIC ACID PROBES.HIV-1: The type species of LENTIVIRUS and the etiologic agent of AIDS. It is characterized by its cytopathic effect and affinity for the T4-lymphocyte.DNA Transposable Elements: Discrete segments of DNA which can excise and reintegrate to another site in the genome. Most are inactive, i.e., have not been found to exist outside the integrated state. DNA transposable elements include bacterial IS (insertion sequence) elements, Tn elements, the maize controlling elements Ac and Ds, Drosophila P, gypsy, and pogo elements, the human Tigger elements and the Tc and mariner elements which are found throughout the animal kingdom.Time Factors: Elements of limited time intervals, contributing to particular results or situations.Sequence Homology, Nucleic Acid: The sequential correspondence of nucleotides in one nucleic acid molecule with those of another nucleic acid molecule. Sequence homology is an indication of the genetic relatedness of different organisms and gene function.Protein Biosynthesis: The biosynthesis of PEPTIDES and PROTEINS on RIBOSOMES, directed by MESSENGER RNA, via TRANSFER RNA that is charged with standard proteinogenic AMINO ACIDS.Retroviridae: Family of RNA viruses that infects birds and mammals and encodes the enzyme reverse transcriptase. The family contains seven genera: DELTARETROVIRUS; LENTIVIRUS; RETROVIRUSES TYPE B, MAMMALIAN; ALPHARETROVIRUS; GAMMARETROVIRUS; RETROVIRUSES TYPE D; and SPUMAVIRUS. A key feature of retrovirus biology is the synthesis of a DNA copy of the genome which is integrated into cellular DNA. After integration it is sometimes not expressed but maintained in a latent state (PROVIRUSES).Colorectal Neoplasms: Tumors or cancer of the COLON or the RECTUM or both. Risk factors for colorectal cancer include chronic ULCERATIVE COLITIS; FAMILIAL POLYPOSIS COLI; exposure to ASBESTOS; and irradiation of the CERVIX UTERI.Gene Silencing: Interruption or suppression of the expression of a gene at transcriptional or translational levels.ras Proteins: Small, monomeric GTP-binding proteins encoded by ras genes (GENES, RAS). The protooncogene-derived protein, PROTO-ONCOGENE PROTEIN P21(RAS), plays a role in normal cellular growth, differentiation and development. The oncogene-derived protein (ONCOGENE PROTEIN P21(RAS)) can play a role in aberrant cellular regulation during neoplastic cell transformation (CELL TRANSFORMATION, NEOPLASTIC). This enzyme was formerly listed as EC 3.6.1.47.RNA: A polynucleotide consisting essentially of chains with a repeating backbone of phosphate and ribose units to which nitrogenous bases are attached. RNA is unique among biological macromolecules in that it can encode genetic information, serve as an abundant structural component of cells, and also possesses catalytic activity. (Rieger et al., Glossary of Genetics: Classical and Molecular, 5th ed)Retinitis Pigmentosa: Hereditary, progressive degeneration of the neuroepithelium of the retina characterized by night blindness and progressive contraction of the visual field.Prognosis: A prediction of the probable outcome of a disease based on a individual's condition and the usual course of the disease as seen in similar situations.Apoptosis: One of the mechanisms by which CELL DEATH occurs (compare with NECROSIS and AUTOPHAGOCYTOSIS). Apoptosis is the mechanism responsible for the physiological deletion of cells and appears to be intrinsically programmed. It is characterized by distinctive morphologic changes in the nucleus and cytoplasm, chromatin cleavage at regularly spaced sites, and the endonucleolytic cleavage of genomic DNA; (DNA FRAGMENTATION); at internucleosomal sites. This mode of cell death serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth.DNA Methylation: Addition of methyl groups to DNA. DNA methyltransferases (DNA methylases) perform this reaction using S-ADENOSYLMETHIONINE as the methyl group donor.Cytoskeletal Proteins: Major constituent of the cytoskeleton found in the cytoplasm of eukaryotic cells. They form a flexible framework for the cell, provide attachment points for organelles and formed bodies, and make communication between parts of the cell possible.Cell Division: The fission of a CELL. It includes CYTOKINESIS, when the CYTOPLASM of a cell is divided, and CELL NUCLEUS DIVISION.Genomic Instability: An increased tendency of the GENOME to acquire MUTATIONS when various processes involved in maintaining and replicating the genome are dysfunctional.

*Non-coding RNA

In higher eukaryotes microRNAs regulate gene expression. A single miRNA can reduce the expression levels of hundreds of genes. ... these patients were noncarriers of BRCA1 or BRCA2 mutations, lending the possibility that familial breast cancer may be caused ... Additionally artificially evolved RNAs also fall under the fRNA umbrella term. Some publications state that ncRNA and fRNA are ... These range from ncRNAs of central importance that are conserved across all or most cellular life through to more transient ...

*Antigenic variation

... brucei BRCA2 gene with RAD51 (however, this is not the only responsible mechanism, as BRCA2 variants still display some VSG ... Switching of VSG proteins occurs at a rate substantially higher than the background mutation rate of other genes in the ... Additionally amino acid co-evolution is a challenging issue that needs to be addressed. For example, a substitution in a ... as well as cellular components of the innate and adaptive immune systems. In order to protect itself from host defenses, the ...

*Causes of cancer

Some of these syndromes include: certain inherited mutations in the genes BRCA1 and BRCA2 with a more than 75% risk of breast ... Additionally, the vast majority of non-invasive cancers are non-melanoma skin cancers caused by non-ionizing ultraviolet ... and this is explained by the observation that many molecular and cellular changes are involved in the development of cancer, so ... even in the absence of a breast-cancer gene. Similarly, men of African ancestry have significantly higher levels of ...

*Synthetic lethality

For example, BRCA1 and BRCA2 are important for repairing double-strand breaks in DNA, and mutations in these genes predispose ... synthetic lethal screens may help illuminate questions about how cellular processes work without previous knowledge of gene ... Additionally, the enolase inhibitor PhAH, with half-maximal inhibitory (IC50) concentrations around 20 nM, proved to be ... Mutations in genes employed in DNA mismatch repair (MMR) cause a high mutation rate. In tumors, such frequent subsequent ...

*Cancer epigenetics

When mutation results in loss of heterozygosity at tumor suppressor gene sites, these genes may become inactive. Single base ... Additionally, increased CpG site methylation was found in low levels in most of the five host nuclear genes studied, including ... Tutt AN, van Oostrom CT, Ross GM, van Steeg H, Ashworth A (March 2002). "Disruption of Brca2 increases the spontaneous mutation ... yet cytosine methylation can lead directly to destabilizing genetic mutations and a precancerous cellular state. Methylated ...

*CHEK2

BRCA2 and CHEK2 gene mutations". Oncogene. 25 (43): 5837-45. doi:10.1038/sj.onc.1209875. PMID 16998498. Nevanlinna H, Bartek J ... Human CHEK2 genome location and CHEK2 gene details page in the UCSC Genome Browser. Molecular and Cellular Biology portal This ... screening of LFS and LFL patients has revealed no or very rare individual missense variants in the CHEK2 gene. Additionally, ... Genes & Development. 12 (3): 382-95. doi:10.1101/gad.12.3.382. PMC 316487 . PMID 9450932. Matsuoka S, Huang M, Elledge SJ (Dec ...

*Minigene

"Comprehensive splicing functional analysis of DNA variants of the BRCA2 gene by hybrid minigenes". Breast Cancer Research. 14 ( ... oncologists have proposed tests designed to detect products of abnormal gene expression for diagnostic purposes. Additionally, ... IGHD type II is an autosomal dominant form caused by a mutation in the intervening sequence (IVS) adjacent to exon 3 of the ... A typical experiment might involve wild type minigenes which are expected to express genes normally in a comparison run against ...

*Breast cancer

This includes those who carry the BRCA1 and BRCA2 gene mutation. These mutations account for up to 90% of the total genetic ... In those with mutations in the breast cancer susceptibility genes BRCA1 or BRCA2, or who have a family history of breast cancer ... Additionally, it is not clear if the association exists with newer hormonal birth controls. ... HER2 causes cellular growth and division; in the absence of stimulation by the growth factor, the cell will normally stop ...

*Ageing

Over-expression of the Ras2 gene increases lifespan in yeast by 30%.[87] A yeast mutant lacking the genes SCH9 and RAS1 has ... "Effects of BRCA1 and BRCA2 mutations on female fertility". Proceedings of the Royal Society B: Biological Sciences. 279 (1732 ... cellular senescence (accumulation of no longer dividing cells in certain tissues, a process induced especially by p16INK4a/Rb ... Public policies and programmes should additionally address the needs of older impoverished people who cannot afford health care ...

*Ageing

Over-expression of the Ras2 gene increases lifespan in yeast by 30%. A yeast mutant lacking the genes sch9 and ras2 has ... Smith, K. R.; Hanson, H. A.; Mineau, G. P.; Buys, S. S. (2011). "Effects of BRCA1 and BRCA2 mutations on female fertility". ... In the broader sense, ageing can refer to single cells within an organism which have ceased dividing (cellular senescence) or ... Public policies and programmes should additionally address the needs of older impoverished people who cannot afford health care ...

*High-grade serous carcinoma

A mutation in BRCA1 or BRCA2 can confer a lifetime ovarian cancer risk of 40-50% and 10-20% respectively, with BRCA2 mutations ... TP53-/- mice (in which the TP53 gene has been deleted) do not develop ovarian carcinomas. However, TP53 mutations were found in ... The majority of these feature mutations in the tumour suppressor BRCA genes, which tend to give rise to HGSC. ... Additionally, overexpression of TP53 is associated with better clinical outcome whereas an absence of the p53 protein is linked ...

*Aurora B kinase

Human AIM1 genome location and AIM1 gene details page in the UCSC Genome Browser. Human AURKB genome location and AURKB gene ... Oddly, mutation of this phosphorylation site in CENP-A leads to defects in cytokinesis. Aurora B also interacts with mitotic ... Aurora B, itself, can also phosphorylate CENP-A at the same residue once it is recruited (see below). Additionally, ... Genes Cells. 7 (1): 11-7. doi:10.1046/j.1356-9597.2001.00498.x. PMID 11856369. Gigoux V, L'Hoste S, Raynaud F, et al. (2002). " ...

*Cancer

Some of these syndromes include: certain inherited mutations in the genes BRCA1 and BRCA2 with a more than 75% risk of breast ... Small-scale mutations include point mutations, deletions, and insertions, which may occur in the promoter region of a gene and ... Additionally, patients with worse prognoses may be depressed or report poorer quality of life because they perceive that their ... The improved understanding of molecular biology and cellular biology due to cancer research has led to new treatments for ...

*Cancer

... certain inherited mutations in the genes BRCA1 and BRCA2 with a more than 75% risk of breast cancer and ovarian cancer,[56] and ... Small-scale mutations include point mutations, deletions, and insertions, which may occur in the promoter region of a gene and ... "Molecular and Cellular Biology. 23 (7): 2225-38. doi:10.1128/MCB.23.7.2225-2238.2003. PMC 150734. PMID 12640109.. / ... Additionally, patients with worse prognoses may be depressed or report poorer quality of life because they perceive that their ...
BRCA1 is a breast cancer susceptibility gene that is down-regulated in a significant proportion of sporadic breast cancers. BRCA1 is posttranscriptionally regulated by RNA-binding proteins, the identities of which are unknown. HuR is an RNA binding protein implicated in posttranscriptional regulation of many genes and is overexpressed in sporadic breast cancer. To investigate the possibility that these two molecules are functionally linked in breast cancer, we performed bioinformatic analysis of the BRCA1 3 untranslated region (UTR), RNA-protein assays with the HuR protein and the BRCA1 3UTR, and immunohistochemical analysis of a cohort of breast tumors using antibodies against BRCA1 and HuR. Here, we describe the identification of two predicted HuR-binding sites in the BRCA1 3UTR, one of which binds specifically to HuR. We also show that this interaction is disrupted by ...
Breast Cancer is very common among Canadians. The Canadian Breast Cancer Foundation reported in 2014 " 1 in 9 women in Canada is expected to develop breast cancer during her lifetime." Today we are focusing on the genetic aspects of developing breast cancer in the body.. BRCA1 and BRCA2 genes - BRCA1 and BRCA 2 known, as a Breast Cancer Susceptibility Gene 1 and Breast Cancer Susceptibility Gene 2 are human genes and works as tumor suppressors.. How BRCA1 and BRCA2 connect to cancer? When any of those genes mutate, it causes DNA damage and it might not be able to repair properly, and as a results cell can develop additional genetic alterations. Inherited mutations in BRCA1 and BRCA2 then increase the risk of breast and ovarian cancer.. NOTE: ...
Given how BRCA2 is believed to function as a tumour suppressor, assays related to DNA repair are directly relevant to predicting the impact of BRCA2 variants on cancer risk and therapeutic response. Additionally, such assays have demonstrated high sensitivity and specificity for predicting known benign and pathogenic variants. For these reasons, DNA repair-related assays are considered here.21 Since DNA repair-related domains are distributed throughout BRCA2, as discussed earlier, such assays should be based on expression of full-length BRCA2. BRCA2 is even larger than BRCA1 (the protein is ~390 kDa and the cDNA is 10 254 bp). Thus, it has been difficult to express full-length BRCA2 in human cells using a cDNA.69 73 As such, some functional studies of BRCA2 VUS have been based on heterologous expression of full-length BRCA2 variants in mouse ...
Looking for online definition of BRCA1/BRCA2-containing complex, subunit 1 in the Medical Dictionary? BRCA1/BRCA2-containing complex, subunit 1 explanation free. What is BRCA1/BRCA2-containing complex, subunit 1? Meaning of BRCA1/BRCA2-containing complex, subunit 1 medical term. What does BRCA1/BRCA2-containing complex, subunit 1 mean?
PURPOSE: We analyzed the expression of critical cell cycle regulators cyclin E and cyclin D1 in familial breast cancer, focusing on BRCA mutation-negative tumors. Cyclin E expression in tumors of BRCA1 or BRCA2 carriers is higher, and cyclin D1 expression lower, than in sporadic tumors. In familial non-BRCA1/2 tumors, cyclin E and cyclin D1 expression has not been studied. EXPERIMENTAL DESIGN: Cyclin E and cyclin D1 immunohistochemical expression was studied in tissue microarrays consisting of 53 BRCA1, 58 BRCA2, 798 familial non-BRCA1/2, and 439 sporadic breast tumors. RESULTS: In univariate analysis, BRCA1 tumors had significantly more frequently high cyclin E (88%) and low cyclin D1 (84%) expression than sporadic (54% and 49%, respectively) or familial non-BRCA1/2 (38% and 45%, respectively) tumors. BRCA2 tumors had significantly more ...
Purpose: Germline mutations in the BRCA1 and BRCA2 genes confer increased risks for breast cancers. However, the clinical presentation of breast cancer among women who are carriers of the BRCA1 or BRCA2 (BRCA1/2 carriers) mutations is heterogenous. We aimed to identify the effects of the reproductive histories of women with the BRCA1/2 mutations on the clinical presentation of breast cancer. Methods: We retrospectively analyzed clinical data on women with proven BRCA1 and BRCA2 mutations who were recruited to the Korean Hereditary Breast Cancer study, from 2007 to 2014. Results: Among the 736 women who were BRCA1/2 mutation carriers, a total of 483 women had breast cancers. Breast cancer diagnosis occurred at significantly younger ages in women who experienced menarche at ≤ ...
Two single nucleotide polymorphisms (SNPs) at 6q25.1, near the ESR1 gene, have been implicated in the susceptibility to breast cancer for Asian (rs2046210) and European women (rs9397435). A genome-wide association study in Europeans identified two further breast cancer susceptibility variants: rs11249433 at 1p11.2 and rs999737 in RAD51L1 at 14q24.1. Although previously identified breast cancer susceptibility variants have been shown to be associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers, the involvement of these SNPs to breast cancer susceptibility in mutation carriers is currently unknown. To address this, we genotyped these SNPs in BRCA1 and BRCA2 mutation carriers from 42 studies from the Consortium of Investigators of Modifiers of BRCA1/2. In the analysis of 14 123 BRCA1 and 8053 BRCA2 mutation carriers of European ancestry, the 6q25.1 SNPs (r(2) ...
Germline mutations in the genes BRCA1 and BRCA2 have been demonstrated in the majority of hereditary breast and ovarian cancer families. The increased risk to develop both breast and ovarian cancer associated with inheriting a BRCA1 or BRCA2 mutation has been well established. It has also been suggested that is an overrepresentation of other cancers such as colon, prostate and pancreatic cancer present in BRCA1 or BRCA2 families. Population specific mutations in BRCA1 and BRCA2 have been identified. In the Ashkenazi Jewish population, 3 specific mutations have been seen in 2% of the population. This study will anonymously screen archived tissue samples of Ashkenazi Jewish individuals diagnosed with cancer between 1993 and 1996 at MSKCC for the three founder mutations seen in the Ashkenazi ...
The 12 tumors with a hypermethylated BRCA1 promoter were also analyzed for the two BRCA1 founder mutations common in the Ashkenazi Jewish population, BRCA1 185delAG (exon 2) and BRCA1 5382 insC (exon 20), and found to be free of mutation (Table 1) ⇓ . These samples were also analyzed and found to be absent for the BRCA2 6174delT (exon 11) Jewish founder mutation. The lack of a Jewish founder mutation does not, however, rule out the possibility that other BRCA1 mutations are present. The absence of BRCA1 protein staining in 2 of 9 unmethylated OCs suggests that mechanisms other than promoter hypermethylation may also inhibit BRCA1 protein expression.. A relationship between the BRCA and p53 genes has long been suspected, based upon the higher incidence of p53 mutations in tumors with ...
Rapid developments in cancer genetics have exposed a knowledge vacuum about genetic testing for susceptibility to cancer. Our experience in testing for BRCA1 or BRCA2 mutation in hereditary breast cancer (HBC) syndrome, with counseling about cancer surveillance and management, inclusive of the option of prophylactic surgery, provides some important information. We provided DNA-based (BRCA1, BRCA2 germ-line mutation) findings on 442 patients from 37 HBC families. The top two reasons for receiving genetic test results are for their children and for their own health surveillance. Of those women who have tested positive for BRCA1 and have been counseled, 40% had already developed breast cancer and 6% had already developed ovarian cancer, while in BRCA2 25% had developed breast cancer and 0% had developed ovarian cancer. Of the unaffected women, prior to ...
TY - JOUR. T1 - Inhibition of BRCT(BRCA1)-phosphoprotein interaction enhances the cytotoxic effect of olaparib in breast cancer cells. T2 - A proof of concept study for synthetic lethal therapeutic option. AU - Pessetto, Ziyan Yuan. AU - Yan, Ying. AU - Bessho, Tadayoshi. AU - Natarajan, Amarnath. PY - 2012/7. Y1 - 2012/7. N2 - Synthetic lethal therapeutic strategy using poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitor olaparib in carriers of BRCA1 or BRCA2 mutation has shown promise in clinical settings. Since ≤5 % of patients are BRCA1 or BRCA2 mutation carriers, small molecules that functionally mimic BRCA1 or BRCA2 mutations will extend the synthetic lethal therapeutic option for non-mutation carriers. Here we provide proof of principle for this strategy using a BRCA1 inhibitor peptide 2 that targets the ...
Background: While BRCA mutation carriers possess a 20-40% lifetime risk of developing ovarian cancer, knowledge about genetic modifying factors influencing the phenotypic expression remains obscure. We explored the distribution of the MDM2 polymorphisms SNP309T>G and the recently discovered SNP285G>C in Norwegian patients with BRCA related ovarian cancer.. G and the recently discovered SNP285G>C in Norwegian patients with BRCA related ovarian cancer.. C in Norwegian patients with BRCA related ovarian cancer.. Methods: 221 BRCA related ovarian cancer cases (BRCA1; n = 161 and BRCA2; n = 60) were tested for the MDM2 polymorphisms. Results were compared to healthy controls (n = 2,465).. Results: The SNP309G allele was associated with elevated OR for ovarian cancer in BRCA1 mutation carriers (SNP309TG: OR 1.53; CI 1.07-2.19; p = 0.020; SNP309GG: OR 1.92; CI ...
About 5% to 10% of breast cancers are thought to be hereditary, caused by abnormal genes passed from parent to child.. Genes are particles in cells, contained in chromosomes, and made of DNA (deoxyribonucleic acid). DNA contains the instructions for building proteins. And proteins control the structure and function of all the cells that make up your body.. Most inherited cases of breast cancer are associated with two abnormal genes: BRCA1 (BReast CAncer gene one) and BRCA2 (BReast CAncer gene two).. Everyone has BRCA1 and BRCA2 genes. The function of the BRCA genes is to repair cell damage and keep breast cells growing normally. But when these genes contain abnormalities or mutations that are passed from generation to generation, the ...
Given that breast cancers in germline BRCA1 carriers are predominantly estrogen-negative and triple-negative, it has been suggested that women diagnosed with triple-negative breast cancer (TNBC) younger than 50 years should be offered BRCA1 testing, regardless of family cancer characteristics. However, the predictive value of triple-negative breast cancer, when taken in the context of personal and family cancer characteristics, is unknown. The aim of this study was to determine whether TNBC is a predictor of germline BRCA1 mutations, in the context of multiple predictive factors. Germline mutations in BRCA1 and BRCA2 were analyzed by Sanger sequencing and multiple ligation-dependent probe amplification (MLPA) analysis in 431 women from the Malaysian Breast Cancer Genetic Study, including 110 women with TNBC. Logistic regression was used to identify and to estimate the ...
Mutations in BRCA1 and BRCA2 are responsible for a large proportion of breast-ovarian cancer families. Protein-truncating mutations have been effectively used in the clinical management of familial breast cancer due to their deleterious impact on protein function. However, the majority of missense variants identified throughout the genes continue to pose an obstacle for predictive informative testing due to low frequency and lack of information on how they affect BRCA1/2 function. Phosphorylation of BRCA1 and BRCA2 play an important role in their function as regulators of DNA repair, transcription and cell cycle in response to DNA damage but whether missense variants of uncertain significance (VUS) are able to disrupt this important process is not known. Here we employed a novel approach using NetworKIN which predicts in vivo kinasesubstrate relationship, and evolutionary ...
While interplay between BRCA1 and AURKA-RHAMM-TPX2-TUBG1 regulates mammary epithelial polarization, common genetic variation in HMMR (gene product RHAMM) may be associated with risk of breast cancer in BRCA1 mutation carriers. Following on these observations, we further assessed the link between the AURKA-HMMR-TPX2-TUBG1 functional module and risk of breast cancer in BRCA1 or BRCA2 mutation carriers. Forty-one single nucleotide polymorphisms (SNPs) were genotyped in 15,252 BRCA1 and 8,211 BRCA2 mutation carriers and subsequently analyzed using a retrospective likelihood approach. The association of HMMR rs299290 with breast cancer risk in BRCA1 mutation carriers was confirmed: per-allele hazard ratio (HR) = 1.10, 95% confidence interval (CI) 1.04-1.15, p = 1.9 x 10(-4) (false discovery rate (FDR)-adjusted p = 0.043). Variation in CSTF1, located next to ...
SNPedia currently contains 2606 BRCA1 SNPs and 3099 BRCA2 SNPs. Some of the variations in these genes are linked to Breast cancer and ovarian cancer, and other variations are benign. See also BRCA1 and BRCA2 for individual gene discussions and links. Microarray platforms used by DTC genomics testing companies such as FamilyTree DNA and 23andMe usually test a fraction of the known BRCA1 or BRCA2 SNPs, typically, the most common ones. While DTC genomics testing may lead to useful results, it is not a substitute for the full genetic panel testing or gene sequencing that may be warranted by a family history of breast cancer. The percent of known BRCA1 and BRCA2 syndrome disease-causing mutations that are tested by several companies is shown in the following table: ...
A breast cancer (BRCA) gene test is a blood test to check for specific changes (mutations) in genes that help control normal cell growth. Finding changes in these genes, called BRCA1 and BRCA2, can help determine your chance of developing breast cancer and ovarian cancer. A BRCA gene test does not test for cancer itself. This test is only done for people with a strong family history of breast cancer, ovarian cancer and sometimes for those who already have one of these diseases. Genetic counseling before and after a BRCA test is very important to help you understand the benefits, risks, and possible outcomes of the test.. A womans risk of breast and ovarian cancer is higher if she has BRCA1 or BRCA2 gene changes. Breast cancer is extremely rare in men but ...
This study aimed to determine whether telomere length (TL) is a marker of cancer risk or genetic status amongst two cohorts of BRCA1 and BRCA2 mutation carriers and controls. The first group was a prospective set of 665 male BRCA1/2 mutation carriers and controls (mean age 53 years), all healthy at time of enrollment and blood donation, 21 of whom have developed prostate cancer whilst on study. The second group consisted of 283 female BRCA1/2 mutation carriers and controls (mean age 48 years), half of whom had been diagnosed with breast cancer prior to enrollment. TL was quantified by qPCR from DNA extracted from peripheral blood lymphocytes. Weighted and unweighted Cox regressions and linear regression analyses were used to assess whether TL was associated with BRCA1/2 mutation status or cancer risk. We found no evidence for association between developing cancer or being a BRCA1 or ...
article{ac3c1e27-9238-408a-9002-fb95610acc6d, abstract = {Introduction - A small fraction of breast cancer is the result of germline mutations in the BRCA1 and BRCA2 cancer susceptibility genes. Mutation carriers frequently have a positive family history of breast and ovarian cancer, are often diagnosed at a young age, and may have a higher incidence of double or multiple primary breast tumours than breast cancer patients in general. Objectives - To estimate the prevalence and spectrum of BRCA1 and BRCA2 mutations in young Danish patients affected with bilateral or multifocal breast cancer and to determine the relationship of mutation status to family history of cancer. Subjects - From the files of the Danish Breast Cancer Cooperative Group (DBCG), we selected 119 breast cancer patients diagnosed before the age of 46 years with either bilateral (n=59) or multifocal (n=61) ...
Background: Understanding the effect of oral contraceptives on risk of breast cancer in BRCA1 or BRCA2 mutation carriers is important because oral contraceptive use is a common, modifiable practice.. Methods: We studied 497 BRCA1 and 307 BRCA2 mutation carriers, of whom 195 and 128, respectively, had been diagnosed with breast cancer. Case-control analyses were conducted using unconditional logistic regression with adjustments for family history and familial relationships and were restricted to subjects with a reference age under 50 years.. Results: For BRCA1 mutation carriers, there was no significant association between risk of breast cancer and use of oral contraceptives for at least 1 year [odds ratio (OR), 0.77; 95% confidence interval (95% CI), 0.53-1.12] or duration of oral contraceptive use (Ptrend = 0.62). For BRCA2 mutation carriers, there was no association with use of oral contraceptives for at ...
TY - JOUR. T1 - Endometrial cancers in mutation carriers from hereditary breast ovarian cancer syndrome kindreds. AU - Casey, Murray J.. AU - Bewtra, Chhanda. AU - Lynch, Henry T.. AU - Snyder, Carrie L.. AU - Stacey, Mark. PY - 2015/5/7. Y1 - 2015/5/7. N2 - Objective The aim of this study was to categorize and report endometrial cancers in mutation carriers from hereditary breast ovarian cancer families. Methods Our Hereditary Cancer Registry was searched for gynecologic and peritoneal cancers linked to mutations in BRCA1 or BRCA2. Invasive cancers were registered in 101 mutation carriers with complete pathology reports. Efforts were made to secure diagnostic surgical pathology tissues for review. All records and available diagnostic slides were meticulously studied, and primary cancers were classified. Findings Eight malignancies were classified as primary endometrial cancers. Five of these were low- or intermediate-grade endometrioid carcinomas, and 3 ...
TY - JOUR. T1 - A high incidence of BRCA1 mutations in 20 breast-ovarian cancer families. AU - Serova, Olga. AU - Montagna, Marco. AU - Torchard, Delphine. AU - Narod, Steven A.. AU - Tonin, Patricia. AU - Sylla, Bakary. AU - Lynch, Henry T.. AU - Feunteun, Jean. AU - Lenoir, Gilbert M.. PY - 1996. Y1 - 1996. N2 - We have analyzed 20 breast-ovarian cancer families, the majority of which show positive evidence of linkage to chromosome 17q12, for germ-line mutations in the BRCA1 gene. BRCA1 mutations cosegregating with breast and ovarian cancer susceptibility were identified in 16 families, including 1 family with a case of male breast cancer. Nine of these mutations have not been reported previously. The majority of mutations were found to generate a premature stop codon leading to the formation of a truncated BRCA1 protein ...
Trypanosoma brucei survives in mammals through antigenic variation, which is driven by RAD51-directed homologous recombination of Variant Surface Glycoproteins (VSG) genes, most of which reside in a subtelomeric repository of |1000 silent genes. A key regulator of RAD51 is BRCA2, which in T. brucei contains a dramatic expansion of a motif that mediates interaction with RAD51, termed the BRC repeats. BRCA2 mutants were made in both tsetse fly-derived and mammal-derived T. brucei, and we show that BRCA2 loss has less impact on the health of the former. In addition, we find that genome instability, a hallmark of BRCA2 loss in other organisms, is only seen in mammal-derived T. brucei. By generating cells expressing BRCA2 variants with altered BRC repeat numbers, we show that the BRC repeat expansion is crucial for RAD51 subnuclear dynamics after DNA damage. Finally, we document ...
Women with hereditary breast cancer predispositions should avoid using their smartphones, tablets and laptops at night Home Women with hereditary breast cancer predispositions should avoid using their smartphones, tablets and laptops at night 09 JAN 18 Women with hereditary breast cancer predispositions should avoid using their smartphones, tablets and laptops at night From SMJ Mortazavi,…
Male breast cancer (MBC) represents a poorly characterised group of tumours, the management of which is largely based on practices established for female breast cancer. However, recent studies demonstrate biological and molecular differences likely to impact on tumour behaviour and therefore patient outcome. The aim of this study was to investigate methylation of a panel of commonly methylated breast cancer genes in familial MBCs. 60 tumours from 3 BRCA1 and 25 BRCA2 male mutation carriers and 32 males from BRCAX families were assessed for promoter methylation by methylation-sensitive high resolution melting in a panel of 10 genes (RASSF1A, TWIST1, APC, WIF1, MAL, RARβ, CDH1, RUNX3, FOXC1 and GSTP1). An average methylation index (AMI) was calculated for each case comprising the average of the methylation of the 10 genes tested as an indicator of overall tumour promoter region methylation. Promoter ...
Hereditary Breast and Ovarian Cancer Syndrome. Hereditary breast and ovarian cancer syndrome is caused by germline mutations in one or both of the autosomal dominant DNA repair genes BRCA1 and BRCA2 (8). Although most cases of breast cancer and ovarian cancer in the United States occur sporadically, BRCA1 and BRCA2 mutations are present in 5-15% of cases of these types of cancer (9). The carrier frequency of hereditary breast and ovarian cancer syndrome is approximately 1 in 500 individuals in the general population, but it has a prevalence of 1 in 40 individuals in the Ashkenazi Jewish population (10). In men, BRCA mutations are associated with breast cancer, prostate cancer, and pancreatic cancer. Therefore, it is important to inquire about maternal and paternal ancestry in male and female relatives. Hereditary breast and ovarian cancer ...
Men with prostate cancer who are carriers of the BRCA2 gene mutation have significantly increased mortality rates.. The study identified 938 families with the BRCA2 mutation, of which 277 (29.5%) contained one or more cases of prostate cancer, with a total of 434 cases. Of these, 67 men were found to carry the familial BRCA2 mutation and 116 were probable mutation carriers. A comparison group of men with the BRCA1 mutation was also identified. Of 1,735 families, 316 contained one or more cases of prostate cancer (18.2%), with a total of 457 cases. Of these, 37 carried the BRCA1 mutation and 82 men were probable carriers. The average age at diagnosis was similar for the two groups.. Survival analysis was performed to establish the overall survival of BRCA2 carriers with prostate cancer and relative survival compared with BRCA1 carriers. The median survival time was 4.0 years ...
Ataxia-telangiectasia mutation (ATM) has previously been shown to be necessary for the phosphorylation of BRCA1 to occur in response to gamma-irradiation, and capable of directly phosphorylating BRCA1 in vitro (see additional information). This paper indicates that ATM can also cause the phosphorylation of BRCA1 by activating the hCds1/CHK2 kinase, for which BRCA1 is a substrate. Phosphorylation of BRCA1 in response to other genotoxins appears to be independent of ATM (Scully et al, Cell 1997, 90: 425-435 [Abstract]). ATM-independent activation of hCds1/CHK2 may explain how some of these other genotoxins cause BRCA1 phosphorylation.. The ATM-hCds1/CHK2-BRCA1 DNA damage response pathway is clearly important for tumour suppression since heterozygous carriers of mutant BRCA1, ATM and hCds1/hCHK2 genes (see additional information) have all been reported to be ...
TY - JOUR. T1 - Genetic testing in an ethnically diverse cohort of high-risk women. T2 - A comparative analysis of BRCA1 and BRCA2 mutations in American families of European and African ancestry. AU - Nanda, Rita. AU - Schumm, L. Philip. AU - Cummings, Shelly. AU - Fackenthal, James D.. AU - Sveen, Lise. AU - Ademuyiwa, Foluso. AU - Cobleigh, Melody. AU - Esserman, Laura. AU - Lindor, Noralane Morey. AU - Neuhausen, Susan L.. AU - Olopade, Olufunmilayo I.. PY - 2005/10/19. Y1 - 2005/10/19. N2 - Context: Ten years after BRCA1 and BRCA2 were first identified as major breast cancer susceptibility genes, the spectrum of mutations and modifiers of risk among many ethnic minorities remain undefined. Objectives: To characterize the clinical predictors, spectrum, and frequency of BRCA1 and BRCA2 mutations in an ethnically diverse ...
Our study reaffirms that specific BRCA1 and BRCA2 mutations found previously to recur in French Canadian breast cancer and breast-ovarian cancer families, also recur in women with ovarian cancer not selected for family history of cancer. This is especially evident with the number of BRCA1:C4446T mutation carriers (n = 15) identified in this study, which has been the most commonly reported mutation identified in this population and this has been attributed to shared ancestry as a consequence of common founders [24,25,27-29,32,33]. This mutation was also the most common mutation found in our previous study of 74 women with serous and endometrioid ovarian cancers screened for specific BRCA1/BRCA2 mutations [36].. Our study also highlights the significance of the BRCA2:E3002K mutation in the French Canadian population. We found five E3002K mutation-positive carriers in the ...
Heterozygous germline mutations in BRCA2 are associated with an increased risk of developing breast and ovarian cancers. BRCA2 is thought to be important for genome stability owing to its involvement in DNA-repair pathways; in addition, previous work has suggested that BRCA2 might regulate cytokinesis, the final step of cell division. Mark Petronczki and colleagues now provide data that disprove this latter hypothesis (p. 1395). Using time-lapse imaging of HeLa cells, the authors show that depletion of BRCA2 abrogates its function in DNA repair but has no effect on cytokinesis. In addition, a diffusion-based assay that precisely discerns the timing of abscission and cell separation shows that BRCA2 does not have a role in these final stages of cytokinesis. Furthermore, DLD1 colon cancer cells in which both BRCA2 alleles are disrupted successfully complete cytokinesis. Finally, the authors ...
In this work, we have demonstrated that human BRCA2 is capable of binding the meiosis‐specific recombinase DMC1 via two different binding sites. The first is located at the C terminus of BRCA2 and corresponds to the region also bound by RAD51 protein. The second, however, represents the primary DMC1 interaction domain located within the relatively uncharacterised central part of BRCA2, contained within B2‐6. Using yeast two‐hybrid assays, pull‐down experiments, and peptide arrays, we defined this interaction domain to the region corresponding to BRCA22386-2411. Within this region, we showed the critical importance of Phe2406, Pro2408, and Pro2409 located in the conserved motif KVFVPPFK, and for simplicity will refer to this DMC1 interaction domain as the PhePP motif.. The PhePP motif of BRCA2 interacts specifically with DMC1, and not with RAD51. The importance of the region is indicated by its conservation in different ...
our genes, which can prevent tumors from forming. When they are functioning properly, they are considered to be tumor suppressors. When mutations occur in the BRCA genes, their function is disrupted. They cannot effectively repair DNA damage, and defects accumulate, making cells more prone to cancer.. Mutations in BRCA are often inherited and people who have them are at increased risk for breast cancer - called inherited breast cancer. But BRCA mutations can also occur sporadically (not inherited). 15-25% of inherited breast cancers are a result of BRCA mutations; however, not all people with the BRCA mutation will get breast cancer.. ...
article{8622899, abstract = {BACKGROUND: Height and body mass index (BMI) are associated with higher ovarian cancer risk in the general population, but whether such associations exist among BRCA1/2 mutation carriers is unknown. METHODS: We applied a Mendelian randomisation approach to examine height/BMI with ovarian cancer risk using the Consortium of Investigators for the Modifiers of BRCA1/2 (CIMBA) data set, comprising 14,676 BRCA1 and 7912 BRCA2 mutation carriers, with 2923 ovarian cancer cases. We created a height genetic score (height-GS) using 586 height-associated variants and a BMI genetic score (BMI-GS) using 93 BMI-associated variants. Associations were assessed using weighted Cox models. RESULTS: Observed height was not associated with ovarian cancer risk (hazard ratio [HR]: 1.07 per 10-cm increase in height, 95% confidence interval [CI]: 0.94-1.23). Height-GS showed similar ...
Germline mutations in the tumor-suppressor gene BRCA2 predispose to breast and ovarian cancer. BRCA2 plays a well-established role in maintaining genome stability by regulating homologous recombination. BRCA2 has more recently been implicated in cytokinesis, the final step of cell division, but the molecular basis for this remains unknown. We have used time-lapse microscopy, recently developed cytokinesis assays and BAC recombineering (bacterial artificial chromosome recombinogenic engineering to investigate the function and localization of BRCA2 during cell division. Our analysis suggests that BRCA2 does not regulate cytokinesis in human cells. Thus, cytokinesis defects are unlikely to contribute to chromosomal instability and tumorigenesis in BRCA2-related cancers. ...
Recent gene expression profiling of breast cancer has identified specific subtypes with clinical, biologic, and therapeutic implications. The basal-like group of tumors is associated with aggressive behavior and poor prognosis, and typically do not express hormone receptors or HER-2 (triple-negative phenotype). Therefore, patients with basal-like cancers do not benefit from currently available targeted systemic therapy.. There is a lot of evidence about a link between basal-like breast cancer and BRCA1 deficiency. Many clinical characteristics and molecular features are shared by basal-like breast cancers and tumors that arise in carriers of BRCA1 germline mutations.. Some studies have indicated that BRCA1 mRNA expression was lower in basal-like sporadic cancers than in controls matched for age and grade. BRCA1 is rarely mutated in sporadic breast cancers and, therefore, it is believed that this may be a ...
Women who inherit mutations in the breast cancer susceptibility genes, BRCA1 and BRCA2, are predisposed to the development of breast and ovarian cancer. We used mice with a Brca1 mutation on a BALB/cJ inbred background (BALB/cB1+/- mice) or a Brca2 genetic alteration on the 129/SvEv genetic background (129B2+/- mice) to investigate potential gene-environment interactions between defects in these genes and treatment with the highly estrogenic compound diethylstilbestrol (DES).. Beginning at 3 weeks of age, BALB/cB1+/-, 129B2+/-, and wild-type female mice were fed a control diet or a diet containing 640 ppb DES for 26 weeks. DES treatment caused vaginal epithelial hyperplasia and hyperkeratosis, uterine inflammation, adenomyosis, and fibrosis, as well as oviductal smooth muscle hypertrophy. The severity of the DES response was mouse strain ...
Author Summary The risk of breast cancer associated with BRCA2 mutations varies widely. To determine whether common genetic variants modify the penetrance of BRCA2 mutations, we conducted the first genome-wide association study of breast cancer among women with BRCA2 mutations using a two-stage approach. The major finding of the study is that only those loci known to be associated with breast cancer risk in the general population, including FGFR2 (rs2981575), modified BRCA2-associated risk in our high-risk population. Two novel loci, on chromosomes 10 in ZNF365 (rs16917302) and chromosome 20 (rs311499), were shown to modify risk in BRCA2 mutation carriers, although not at a genome-wide level of significance. However, the ZNF365 locus has recently independently been associated with breast cancer risk in sporadic tumors, highlighting the ...
Modular domains of proteins are important in cellular signaling processes. Eukaryotic cells are constantly undergoing DNA damage due to exogenous and endogenous sources of damage. The DNA damage response (DDR) involves a complex network of signaling events mediated by modular domains such as the BRCT (BRCA1 C-terminal) domains. Therefore, proteins containing BRCT domains are important for DNA damage detection and signaling. In this dissertation, we focus on two BRCT-containing proteins BRCA1 and PAXIP1. BRCA1 is a gene that is known to be associated with increased risk of hereditary breast and ovarian cancer. Germline variants of BRCA1 are assessed to determine lifetime risk of developing breast and ovarian cancer. This is performed by genetic testing of the BRCA1 sequence and the variants can be classified as pathogenic, non-pathogenic or variants of unknown significance ...
article{a2927d4d-d515-499a-8b73-8d202fc294c4, abstract = {Dedicated clinics have been established for the early diagnosis and treatment of women at risk for inherited breast cancer, but the effects of such interventions are currently unproven. This second report on prospectively diagnosed inherited breast cancer from the European collaborating centres supports the previous conclusions and adds information on genetic heterogeneity and the effect of oophorectomy. Of 249 patients, 20% had carcinoma in situ (CIS), 54% had infiltrating cancer without spread (CaNO) and 26% had cancer with spread (CaN+). Five-year survival was 100% for CIS, 94% for CaNO and 72% for CaN+ (p = 0.007). Thirty-six patients had BRCA1 mutations, and 8 had BRCA2 mutations. Presence of BRCA1 mutation was associated with infiltrating cancer, high grade and lack of oestrogen receptor (p < 0.05 for all 3 characteristics). ...
Short Interspersed Nuclear Elements (SINEs) are non-autonomous retrotransposons that comprise a large fraction of the human genome. SINEs are demethylated in human disease, but whether SINEs become transcriptionally induced and how the resulting transcripts may affect the expression of protein coding genes is unknown. Here, we show that downregulation of the mRNA of the tumor suppressor gene BRCA1 is associated with increased transcription of SINEs and production of sense and antisense SINE small RNAs. We find that BRCA1 mRNA is post-transcriptionally down-regulated in a Dicer and Drosha dependent manner and that expression of a SINE inverted repeat with sequence identity to a BRCA1 intron is sufficient for downregulation of BRCA1 mRNA. These observations suggest that transcriptional activation of SINEs could contribute to a novel mechanism of RNA mediated post-transcriptional silencing of human ...
Obesity is associated with increased breast cancer (BrCA) incidence. an important cell type of the breast microenvironment we examined the impact of adipocyte ERα deletion on cancer cell behavior. Conditioned medium from ERα-null adipocytes and medium containing pure Lcn2 increased proliferation and migration of a subset of BrCA cells in culture. The proliferative and promigratory effects of ERα-deficient adipocyte-conditioned medium on BrCA cells was reversed by deletion. BrCA cell responsiveness to exogenous Lcn2 was heightened in cell types where endogenous expression was minimal but components of the Lcn2 signaling pathway were enriched and 3-hydroxybutyrate dehydrogenase (expression was positively associated with adiposity and circulating Lcn2 levels. Collectively these data suggest that reduction of ERα expression in adipose tissue promotes adiposity and is linked P005672 HCl with the progression and severity of BrCA ...
TY - JOUR. T1 - Emotional impact on the results of BRCA1 and BRCA2 genetic test. T2 - An observational retrospective study. AU - Mella, Sara. AU - Muzzatti, Barbara. AU - Dolcetti, Riccardo. AU - Annunziata, Maria Antonietta. PY - 2017/10/2. Y1 - 2017/10/2. N2 - Background: BRCA1 and BRCA2 mutations are associated with a higher risk of breast and ovarian tumors. This study evaluated the emotional states of women 1 month after having received the results of the genetic test and assessed eventual associations with the type of outcome, personal/familiar disease history and major socio-demographic variables. Methods: The study, an observational retrospective one, involved 91 women, evaluated 1 month after receiving their results. Patients were administered the Hospital Anxiety and Depression Scale, the Profile of Mood States and emotional Thermometers. Results: Anxiety was significantly higher ...
BRCA1 and BRCA2 (BRCA1/2) genes are well-established breast cancer susceptibility genes. A large number of variants in these genes has been reported, including variants with clearly deleterious effects and variants with unknown significance on breast cancer risk. Classification of such unclassified variants (UVs) is an area of growing interest, but no study has systematically assessed whether the various classification methods are biologically meaningful. Further, given that not all BRCA1/2 deleterious mutation carriers develop breast cancer, environmental modifiers of breast cancer risk in BRCA1/2 mutation carriers need to be identified. In this dissertation, I present results from a population-based case-control study of young breast cancer patients to investigate these issues.; In my first paper, I used sequencing data of BRCA1/2 genes in ...
BRCA1 and BRCA2 (BRCA1/2) genes are well-established breast cancer susceptibility genes. A large number of variants in these genes has been reported, including variants with clearly deleterious effects and variants with unknown significance on breast cancer risk. Classification of such unclassified variants (UVs) is an area of growing interest, but no study has systematically assessed whether the various classification methods are biologically meaningful. Further, given that not all BRCA1/2 deleterious mutation carriers develop breast cancer, environmental modifiers of breast cancer risk in BRCA1/2 mutation carriers need to be identified. In this dissertation, I present results from a population-based case-control study of young breast cancer patients to investigate these issues.; In my first paper, I used sequencing data of BRCA1/2 genes in ...
Highlights:. BRCA1 and BRCA2 analysis by Karyo. BRCA1 and BRCA2 are analyzed using CE-IVD kits in our Next Generation Sequencing platform. Full coverage can be obtained by ordering addition large rearrangement analysis of the two genes by means of MLPA analysis.. Human Breast Cancer Panel by Karyo. 19 genes associated with human breast cancer are analyzed using Next Generation Sequencing. The probes are designed to enrich for all the coding exons and splicing sites of these 19 genes. Copy number variation analysis is also included.. The analyzed genes are: AR, ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, DIRAS3, HER2, NBN, PALB2, PTEN, RAD50, RAD51, STK11, TP53, CASP8 και TGFB1.. Exome Analysis - Breast Cancer associated. Hereditary Breast and Ovarian Cancer predominately caused by ...
An analysis of the GeparSixto trial in triple-negative breast cancer showed that adding carboplatin to neoadjuvant therapy improved pathologic complete response rate in patients without BRCA1/2 mutation and that response rates were higher overall in those with mutations, without additive effects observed for carboplatin. The analysis was reported by Hahnen et al in JAMA Oncology. GeparSixto showed the addition of neoadjuvant carboplatin to anthracycline, taxane, and bevacizumab (Avastin) increased pathologic complete response rates among all patients.. Study Details The current analysis included 291 patients, of whom 146 received carboplatin. Pathogenic BRCA1 and BRCA2 germline mutations were present in 50 patients (17.2%), including 26 patients who received carboplatin and 24 patients who did not.. Pathologic Complete Response Rate. The pathologic complete response rate was 56.8% in the carboplatin group vs 41.4% in the ...
In recent years, significant effort has been made to identify genes that influence breast cancer risk. Because the high-penetrance breast cancer susceptibility genes BRCA1 and 2 play a role only in a small fraction of breast cancer cases, understanding the genetic risk of the majority of breast cancers will require the identification and analysis of several lower penetrance genes. The estrogen-signaling pathway plays a crucial role in the pathophysiology of breast cancer; therefore, polymorphism in genes involved in this pathway is likely to influence breast cancer risk. Our detailed analysis of gene expression profiles of estrogen- and 4-OH-tamoxifen-treated ZR75-1 breast cancer cells identified members of the sulfotransferase 1A (SULT1A) phenol sulfotransferase family as downstream targets of tamoxifen. On the basis of the induction of SULT1A by 4-OH-tamoxifen and the known inherited ...
Introduction: Several common alleles have been shown to be associated with breast and/or ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Recent genome-wide association studies of breast cancer have identified eight additional breast cancer susceptibility loci: rs1011970 (9p21, CDKN2A/B), rs10995190 (ZNF365), rs704010 (ZMIZ1), rs2380205 (10p15), rs614367 (11q13), rs1292011 (12q24), rs10771399 (12p11 near PTHLH) and rs865686 (9q31.2). Methods: To evaluate whether these single nucleotide polymorphisms (SNPs) are associated with breast cancer risk for BRCA1 and BRCA2 carriers, we genotyped these SNPs in 12,599 BRCA1 and 7,132 BRCA2 mutation carriers and analysed the associations with breast cancer risk within a retrospective likelihood framework. Results: Only SNP rs10771399 near PTHLH was associated with breast cancer risk for BRCA1 mutation carriers (per-allele hazard ratio (HR) = ...
Introduction: Several common alleles have been shown to be associated with breast and/or ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Recent genome-wide association studies of breast cancer have identified eight additional breast cancer susceptibility loci: rs1011970 (9p21, CDKN2A/B), rs10995190 (ZNF365), rs704010 (ZMIZ1), rs2380205 (10p15), rs614367 (11q13), rs1292011 (12q24), rs10771399 (12p11 near PTHLH) and rs865686 (9q31.2). Methods: To evaluate whether these single nucleotide polymorphisms (SNPs) are associated with breast cancer risk for BRCA1 and BRCA2 carriers, we genotyped these SNPs in 12,599 BRCA1 and 7,132 BRCA2 mutation carriers and analysed the associations with breast cancer risk within a retrospective likelihood framework. Results: Only SNP rs10771399 near PTHLH was associated with breast cancer risk for BRCA1 mutation carriers (per-allele hazard ratio (HR) = ...
Homologous recombination (HR) is essential for the accurate repair of DNA double-strand breaks (DSBs), potentially lethal lesions. HR takes place in the late S-G2 phase of the cell cycle and involves the generation of a single-stranded region of DNA, followed by strand invasion, formation of a Holliday junction, DNA synthesis using the intact strand as a template, branch migration and resolution. It is investigated that RecA/Rad51 family proteins play a central role. The breast cancer susceptibility protein Brca2 and the RecQ helicase BLM (Bloom syndrome mutated) are tumor suppressors that maintain genome integrity, at least in part, through HR ...
Homologous recombination (HR) is essential for the accurate repair of DNA double-strand breaks (DSBs), potentially lethal lesions. HR takes place in the late S-G2 phase of the cell cycle and involves the generation of a single-stranded region of DNA, followed by strand invasion, formation of a Holliday junction, DNA synthesis using the intact strand as a template, branch migration and resolution. It is investigated that RecA/Rad51 family proteins play a central role. The breast cancer susceptibility protein Brca2 and the RecQ helicase BLM (Bloom syndrome mutated) are tumor suppressors that maintain genome integrity, at least in part, through HR ...
This study confirms previous reports that BRCA2 mutation carriers have an increased risk of developing pancreatic cancer compared with the general population. It also supports previous evidence that BRCA1 mutation carriers have increased pancreatic cancer risk, but with a higher relative risk than that estimated by other studies. Furthermore, the availability of a large number of high-risk pancreatic cancer families negative for BRCA1 and BRCA2 mutations (∼5,200) has provided a unique opportunity to estimate pancreatic cancer risk in non-mutation carriers from families with breast and ovarian cancer.. The association between BRCA2 mutations and pancreatic cancer risk has been previously investigated; individuals from BRCA2 mutation carrier families have been reported to have a pancreatic cancer risk ranging from 2- to 7-fold higher than ...
FDCS is a rare tumour with a spectrum of clinical behaviour. While some reports describe an indolent disease [4], others report higher rates of recurrence, metastases and mortality [5, 7]. There are a number of pathological features associated with a poorer prognosis, including size ≥6 cm, coagulative necrosis, high mitotic counts (≥5 per 10 high power field), significant cytologic atypia, younger age and abdominal involvement [5, 6, 15]. As molecular information becomes more readily available for this tumour type, it will also be important to determine its correlation with natural history and therapeutic significance.. This case report describes the use of a PARP inhibitor in combination with carboplatin in the treatment of a FDCS with a BRCA2 mutation. This is the first report of FDCS with a BRCA2 mutation and also the first report of the use of molecularly targeted therapy in this disease. BRCA2 is a tumour suppressor gene involved in ...
Recent Genome-Wide Association Studies (GWAS) have identified four low-penetrance ovarian cancer susceptibility loci. We hypothesized that further moderate- or low-penetrance variants exist among the subset of single-nucleotide polymorphisms (SNPs) not well tagged by the genotyping arrays used in the previous studies, which would account for some of the remaining risk. We therefore conducted a time- and cost-effective stage 1 GWAS on 342 invasive serous cases and 643 controls genotyped on pooled DNA using the high-density Illumina 1M-Duo array. We followed up 20 of the most significantly associated SNPs, which are not well tagged by the lower density arrays used by the published GWAS, and genotyping them on individual DNA. Most of the top 20 SNPs were clearly validated by individually genotyping the samples used in the pools. However, none of the 20 SNPs replicated when tested for association in a much larger stage 2 set of 4,651 cases and 6,966 controls from the Ovarian Cancer Association Consortium.
Germline genetic testing of BRCA1 and BRCA2 is available to identify individuals at increased risk for breast and ovarian cancers, as individuals with an inherited cancer syndrome may benefit from screening and prevention strategies to reduce their risk. The prevalence of BRCA mutations in the population is estimated between 1 in 300 and 1 in 800; however, specific mutations known as founder mutations occur more often in populations founded by a small ancestral group, including Ashkenazi (Eastern European) Jews, French Canadians, and Icelanders. The prevalence of BRCA mutations in the Ashkenazi Jewish population is approximately 1 in 40. Three recurrent BRCA1 and BRCA2 mutations have been identified in Ashkenazi Jewish individuals (i.e., a genetically distinct population of Jewish people of ...
The studys author, Professor Diana Eccles, of the University of Southampton, said: "Women diagnosed with early breast cancer who carry a BRCA mutation are often offered double mastectomies soon after their diagnosis or chemotherapy treatment.. "However, our findings suggest that this surgery does not have to be immediately undertaken along with the other treatment.". Surgery may still be beneficial for patients to reduce their risk in the longer term, such as two to three decades after their initial diagnosis.. Fiona MacNeill, of the Royal Marsden NHS Foundation Trust, who was not involved in the research, said: "This study can reassure young women with breast cancer, particularly those with triple negative cancer or who are BRCA carriers, that breast conservation with radiotherapy is a safe option in the first decade after diagnosis and double mastectomy is not essential or mandatory at initial treatment.. She added: "In view of this, younger women with breast cancer can ...
The studys author, Professor Diana Eccles, of the University of Southampton, said: "Women diagnosed with early breast cancer who carry a BRCA mutation are often offered double mastectomies soon after their diagnosis or chemotherapy treatment.. "However, our findings suggest that this surgery does not have to be immediately undertaken along with the other treatment.". Surgery may still be beneficial for patients to reduce their risk in the longer term, such as two to three decades after their initial diagnosis.. Fiona MacNeill, of the Royal Marsden NHS Foundation Trust, who was not involved in the research, said: "This study can reassure young women with breast cancer, particularly those with triple negative cancer or who are BRCA carriers, that breast conservation with radiotherapy is a safe option in the first decade after diagnosis and double mastectomy is not essential or mandatory at initial treatment. She added: "In view of this, younger women with breast cancer can ...
The studys author, Professor Diana Eccles, of the University of Southampton, said: "Women diagnosed with early breast cancer who carry a BRCA mutation are often offered double mastectomies soon after their diagnosis or chemotherapy treatment.. "However, our findings suggest that this surgery does not have to be immediately undertaken along with the other treatment.". Surgery may still be beneficial for patients to reduce their risk in the longer term, such as two to three decades after their initial diagnosis.. Fiona MacNeill, of the Royal Marsden NHS Foundation Trust, who was not involved in the research, said: "This study can reassure young women with breast cancer, particularly those with triple negative cancer or who are BRCA carriers, that breast conservation with radiotherapy is a safe option in the first decade after diagnosis and double mastectomy is not essential or mandatory at initial treatment. She added: "In view of this, younger women with breast cancer can ...
Western men who carry a BRCA2 genetic mutation have a six to nine per cent lifetime risk of developing breast cancer, UK researchers have found. The team discovered that men with a faulty BRCA2 gene had a 7.1 per cent chance of developing the disease by 70 and an 8.4 per cent chance by the age of 80.. The study, published online in the Journal of Medical Genetics, was the largest and most comprehensive completed to date on BRCA2 and male breast cancer.. This is a reasonably strong risk for men carrying a faulty BRCA2 gene when considering the average risk of breast cancer for men generally is 1-in-1,000, said lead author Gareth Evans, Professor of Medical Genetics at St Marys Hospital in Manchester.. The findings challenge the common perception that breast cancer is an exclusively female health concern, Professor Evans told BioNews.. Men ...
Hereditary Cancer Syndromes can be caused by faulty changes in genes called as "Hereditary Mutations." These can be passed down from parent to child and cause cancer to run in the family, making it a Hereditary Cancer. Women who carry a mutation in either of BRCA genes have a condition called Hereditary Breast Ovarian Cancers (HBOC) syndrome. Approximately 10-15 percent of Ovarian cancer cases and 10 percent of Breast cancer cases are caused by mutations in the BRCA1 or BRCA2 genes. Some more genes have also been found to be responsible for Hereditary Breast or Ovarian Cancer. In addition, mutation carriers who have already been diagnosed with cancer have a significantly increased risk of developing a second cancer in the future.. Lynch Syndrome is also called Hereditary Non Polyposis Colon Cancer (HNPCC). It caused by mutations in the MLH1, ...
Angelina Jolie, in a New York Times article entitled "My Medical Choice,"1 disclosed that having a BRCA1 mutation and an estimated 87% risk of breast cancer, "I decided to be proactive and minimize the risk as much I could. I made a decision to have a preventive double mastectomy." She was writing about it, she explained, "because I hope that other women can benefit from my experience.". The many media reports about Ms. Jolies choice mean that many women have undoubtedly learned about her experience, but the impact remains uncertain. Some commentators have applauded Ms. Jolies decision to speak out about the issue, while others have expressed concern that it could lead to an increase in women seeking unnecessary treatment.. Good Message and Model. Ms. Jolies article presents "a good message," Todd M. Tuttle, MD, MS, told The ASCO Post. He noted that the "red flags" in Ms. Jolies history-her mother died of cancer at age 56, and Ms. Jolie carries a BRCA1 mutation-were ...
The U.S. Food and Drug Administration (FDA) has granted accelerated approval to Rubraca™ (rucaparib) for the treatment of women with advanced ovarian cancer who have been treated with two or more chemotherapies and whose tumors have a BRCA gene mutation.. Each year in the U.S. roughly 22,000 women are diagnosed with ovarian cancer and more than 15,000 die of the disease. Approximately 15 to 20 percent of patients with ovarian cancer have a BRCA gene mutation.. BRCA genes are involved with repairing damaged DNA and normally work to prevent tumor development. However, mutations of these genes may lead to certain cancers, including ovarian cancers. Rubraca is a poly ADP-ribose polymerase (PARP) inhibitor that blocks an enzyme involved in repairing damaged DNA. By blocking this enzyme, DNA inside the cancerous cells with damaged BRCA genes may ...
Recognition of early changes in the Fallopian tube cells of BRCA gene mutation carriers may be key to new strategies for preventing ovarian cancer that could also reduce the need for invasive surgery.
BACKGROUND: Breast cancer (BC) is primarily considered a genetic disorder with a complex interplay of factors including age, gender, ethnicity, family history, personal history and lifestyle with associated hormonal and non-hormonal risk factors. The SNP rs2910164 in miR146a (a G to C polymorphism) was previously associated with increased risk of BC in cases with at least a single copy of the C allele in breast cancer, though results in other cancers and populations have shown significant variation. METHODS: In this study, we examined this SNP in an Australian sporadic breast cancer population of 160 cases and matched controls, with a replicate population of 403 breast cancer cases using High Resolution Melting. RESULTS: Our analysis indicated that the rs2910164 polymorphism is associated with breast cancer risk in both primary and replicate populations (p=0.03 and 0.0013, respectively). In contrast to the results of familial breast cancer studies, however, we found that the presence of the ...
Introduction: Triple negative breast cancers (TNBC) represent 10 to 15% of all breast cancers. This subtype is caracterized by the absence of the expression of estrogen receptor (ER), progesterone receptor (PR) and the absence of Her2 overexpression. TNBC has poor prognosis and does not respond to endocrine therapy or trastuzumab. The BRCA1 gene plays a key role in TNBC, where its expression can be lost in multiple ways: germinal mutation followed by deletion of the second allele, or negative regulations by promoter methylation or miRNA-mediated silencing. BRCA1-deficient tumours exhibit defect in DNA repair and respond to DNA-damaging chemotherapy or PARP inhibitors. We aimed to establish a correlation between BRCA1-related molecular parameters, other tumor characteristics and clinical follow up in order to better classify TNBC and define prognostic factors.. Method: In the tumoral tissues of 60 TNBC patients, the expression of ...
Damayanti, Z., Ilancheran, A., Ali, A.B., Sng, J.H., Iau, P.T.C. (2006). The founder mutation BRCA1c.2845insA identified in a fallopian tube cancer patient: A case report. International Journal of Gynecological Cancer 16 (SUPPL. 1) : 362-365. [email protected] Repository. https://doi.org/10.1111/j.1525-1438.2006.00221. ...
In women, breast cancer awareness should begin at 18 years of age. Females should become familiar with their breasts and should report changes to their healthcare provider if noticed. It should be recommended to female patients that self-breast exam is most informative when performed at the end of menses.. Clinical breast exam should begin at age 25 and occur every 6 to 12 months.. Breast screening recommendations vary based on age:. Age 25 to 29 years: Annual breast MRI (performed days 7-15 of menstrual cycle) or mammogram screening (only if breast MRI is unavailable). Age 30-75 years: Annual mammography and breast MRI screening alternating every six months. Age ,75 years: Management should be considered on an individual basis. Prophylactic risk-reducing mastectomy should be considered as treatment as well.. Regarding monitoring for ovarian cancer, patients should consider the risk-reducing salpingo-oophorectomy, ideally between the ages of 35 and 40 years, upon completion of ...
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Breast surgery and breast reconstruction, oncological surgery, litigation in breast surgery, skin lesions/soft tissue tumours, benign breast change/screening, developmental breast problems and BRCA / high breast cancer risk monitoring, day case surgery, intraoperative radiotherapy for breast cancer, breast augmentation/breast reduction, lumps, bumps and nodules, risk reducing mastectomy - prophylactic breast surgery, salivary gland and lymph node surgery, gynaecomastia/male breast problems ...
Recently, a locus on chromosome 6q22.33 (rs2180341) was reported to be associated with increased breast cancer risk in the Ashkenazi Jewish (AJ) population, and this association was also observed in populations of non-AJ European ancestry. In the present study, we performed a large replication analysis of rs2180341 using data from 31,428 invasive breast cancer cases and 34,700 controls collected from 25 studies in the Breast Cancer Association Consortium (BCAC). In addition, we evaluated whether rs2180341 modifies breast cancer risk in 3,361 BRCA1 and 2,020 BRCA2 carriers from 11 centers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Based on the BCAC data from women of European ancestry, we found evidence for a weak association with breast cancer risk for rs2180341 (per-allele odds ratio (OR) = 1.03, 95% CI 1.00-1.06, p = 0.023). There was evidence for heterogeneity in the ORs among studies (I(2) = 49.3%; p ...
Poly(ADP-ribose) polymerase (PARP) is a critical DNA repair enzyme involved in DNA single-strand break repair via the base excision repair pathway. PARP inhibitors have been shown to sensitize tumors to DNA-damaging agents and to also selectively kill homologous recombination repair-defective cancers, such as those arising in BRCA1 and BRCA2 mutation carriers. Recent proof-of-concept clinical studies have demonstrated the safety and substantial antitumor activity of the PARP inhibitor, olaparib in BRCA1/2 mutation carriers, highlighting the wide therapeutic window that can be achieved with this synthetic lethal strategy. Likewise, the PARP inhibitor, BSI-201, in combination with carboplatin and gemcitabine have produced promising results in "triple-negative" breast cancers. There are also currently numerous other PARP inhibitors in clinical development. The potential broader therapeutic application of these approaches to a wide range of sporadic tumors ...
Cowden syndrome (CS) or multiple hamartoma syndrome (MIM 158350) is an autosomal dominant disorder with an increased risk for breast and thyroid carcinoma. The diagnosis of CS, as operationally defined by the International Cowden Consortium, is made when a patient, or family, has a combination of pathognomonic major and/or minor criteria. The CS gene has recently been identified as PTEN, which maps at 10q23.3 and encodes a dual specificity phosphatase. PTEN appears to function as a tumour suppressor in CS, with between 13-80% of CS families harbouring germline nonsense, missense, and frameshift mutations predicted to disrupt normal PTEN function. To date, only a small number of tumour suppressor genes, including BRCA1, BRCA2, and p53, have been associated with familial breast or breast/ovarian cancer families. Given the involvement of PTEN in CS, we postulated that PTEN was a likely candidate to play a role in families with ...
Suppressor of fused homolog is a protein that in humans is encoded by the SUFU gene. SUFU encodes a component of the sonic hedgehog (SHH) / patched (PTCH) signaling pathway. Mutations in genes encoding components of this pathway are deleterious for normal development and are associated with cancer-predisposing syndromes (e.g., holoprosencephaly, HPE3; basal cell nevus syndrome, BCNS; and Greig cephalopolysyndactyly syndrome; GCPS). SUFU has been shown to interact with GLI1, GLI3 and PEX26. GRCh38: Ensembl release 89: ENSG00000107882 - Ensembl, May 2017 GRCm38: Ensembl release 89: ENSMUSG00000025231 - Ensembl, May 2017 "Human PubMed Reference:". "Mouse PubMed Reference:". Merchant M, Vajdos FF, Ultsch M, Maun HR, Wendt U, Cannon J, Desmarais W, Lazarus RA, de Vos AM, de Sauvage FJ (Sep 2004). "Suppressor of fused regulates Gli activity through a dual binding mechanism". Mol Cell Biol. 24 (19): 8627-41. doi:10.1128/MCB.24.19.8627-8641.2004. PMC 516763 . PMID ...
Mutations caused by DNA damage are a main driver of cancer. We discovered that recognition of newly synthesised histone H4 directs breast cancer type 1 susceptibility protein (BRCA1) to post-replicative chromatin. The switch from mutagenic to error-free DNA double strand break repair by homologous recombination is therefore controlled by chromatin. ...
Abstract: Poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors have shown clinical activity in epithelial ovarian cancer, leading both the US Food and Drug Administration (FDA) and the European Medicines Agency to approve olaparib for tumors characterized by BRCA1 and BRCA2 mutations. However, it is becoming increasingly evident that tumors that share molecular features with BRCA-mutant tumors-a concept known as BRCAness-also may exhibit defective homologous recombination DNA repair, and therefore will respond to PARP inhibition. A number of strategies have been proposed to identify BRCAness, including identifying defects in other genes that modulate homologous recombination and characterizing the mutational and transcriptional signatures of BRCAness. In addition to olaparib, a number of other PARP inhibitors are in clinical development. This article reviews the ...
Metalloprotease that specifically cleaves Lys-63-linked polyubiquitin chains (PubMed:19214193, PubMed:20656690, PubMed:24075985, PubMed:26344097). Does not have activity toward Lys-48-linked polyubiquitin chains. Component of the BRCA1-A complex, a complex that specifically recognizes Lys-63-linked ubiquitinated histones H2A and H2AX at DNA lesions sites, leading to target the BRCA1-BARD1 heterodimer to sites of DNA damage at double-strand breaks (DSBs). In the BRCA1-A complex, it specifically removes Lys-63-linked ubiquitin on histones H2A and H2AX, antagonizing the RNF8-dependent ubiquitination at double-strand breaks (DSBs) (PubMed:20656690). Catalytic subunit of the BRISC complex, a multiprotein complex that specifically cleaves Lys-63-linked ubiquitin in various substrates (PubMed:20656690, PubMed:24075985, PubMed:26344097, PubMed:26195665). Mediates the specific Lys-63-specific deubiquitination associated with the COP9 signalosome complex (CSN), via ...
Variation in penetrance estimates for BRCA1/2 carriers suggests that other environmental and genetic factors may modify cancer risk in carriers. The GSTM1, T1 and P1 isoenzymes are involved in metabolism of environmental carcinogens. The GSTM1 and GSTT1 gene is absent in a substantial proportion of the population. In GSTP1, a single-nucleotide polymorphism that translates to Ile112Val was associated with lower activity. We studied the effect of these polymorphisms on breast cancer (BC) risk in BRCA1/2 carriers. A population of 320 BRCA1/2 carriers were genotyped; of them 262 were carriers of one of the three Ashkenazi founder mutations. Two hundred and eleven were affected with BC (20 also with ovarian cancer (OC)) and 109 were unaffected with BC (39 of them had OC). Risk analyses were conducted using Cox proportional hazard models adjusted for origin (Ashkenazi vs non-Ashkenazi). We found an estimated BC HR ...
Involved in the homologous recombination repair (HRR) pathway of double-stranded DNA, thought to repair chromosomal fragmentation, translocations and deletions. Part of the RAD21 paralog protein complex CX3 which acts in the BRCA1-BRCA2-dependent HR pathway. Upon DNA damage, CX3 acts downstream of RAD51 recruitment; the complex binds predominantly to the intersection of the four duplex arms of the Holliday junction (HJ) and to junctions of replication forks. Involved in HJ resolution and thus in processing HR intermediates late in the DNA repair process; the function may be linked to the CX3 complex and seems to involve GEN1 during mitotic cell cycle progression. Part of a PALB2-scaffolded HR complex containing BRCA2 and RAD51C and which is thought to play a role in DNA repair by HR. Plays a role in regulating mitochondrial DNA copy number under conditions of oxidative stress in the presence of RAD51 and RAD51C. ...
Breast cancer in men is rare - less than 1 percent of all breast carcinomas occur in men. Consider the latest statistics available from the American Cancer Society:. The American Cancer Society estimates that in 2008 some 1,990 new cases of invasive breast cancer will be diagnosed among men in the US.. Breast cancer is about 100 times more common among women.. Estimates for 2008 also indicate that there will be more than 40,930 deaths from breast cancer in the US (40,480 women, 450 men).. The average age at diagnosis is 67, although men can be affected at any age.. Risk factors may include radiation exposure, estrogen administration, diseases associated with hyperestrogenism, such as cirrhosis or Klinefelters syndrome, and heavy alcohol intake.. Also, there are definite familial tendencies for developing breast cancer including an increased incidence in men who have a number of female relatives with breast cancer; an increased risk of male breast cancer has been reported in families in which a ...
Veliparib combined with carboplatin (VC) was an experimental regimen evaluated in the biomarker-rich neoadjuvant I-SPY 2 trial for breast cancer. VC showed improved efficacy in the triple negative signature. However, not all triple negative patients achieved pathologic complete response and some HR+HER2- patients responded. Pre-specified analysis of five DNA repair deficiency biomarkers (BRCA1/2 germline mutation; PARPi-7, BRCA1ness, and CIN70 expression signatures; and PARP1 protein) was performed on 116 HER2- patients (VC: 72 and concurrent controls: 44). We also evaluated the 70-gene ultra-high risk signature (MP1/2), one of the biomarkers used to define subtype in the trial. We used logistic modeling to assess biomarker performance. Successful biomarkers were combined using a simple voting scheme to refine the predicted sensitive group and Bayesian modeling used to estimate the pathologic complete response rates. BRCA1/2 germline ...
Eat a healthy diet. Certain vitamins and minerals have been shown to be beneficial in cancer prevention. They include vitamin A, which is found in leafy green vegetables like spinach, broccoli and brussel sprouts; vitamin D found in milk, cereals and egg yolks; vitamin E found in some oils, whole grains and wheat germ; and Omega-3 fatty acids found in fish such as tuna, salmon and trout.. Get screened. About 25 percent of women diagnosed with ovarian cancer have a hereditary tendency to develop the disease. Most of the time, the patients have a genetic mutation of either the breast cancer gene 1 (BRCA1) or breast cancer gene 2 (BRCA2).. Getting screened for these mutations could lead to an earlier diagnosis and thus, a greater likelihood of successful treatment. Regardless of whether you get screened or not, if you have symptoms have your doctor do a complete physical exam where he or she can detect enlarged ...
The researchers observed that all the patients developed tumors in areas of their breasts next to where they carried their cell phones, often for up to 10 hours per day, for several years. None of the patients had a family history of breast cancer. They all tested negative for BRCA1 and BRCA2 - breast cancer genes linked to about one-half of breast cancer cases - and they had no other known breast cancer risks ...
The second recently approved drug is olaparib, which is indicated as monotherapy for women who have germline BRCA mutations and have been treated with 3 or more lines of previous chemotherapy. Olaparib is an inhibitor of the enzyme poly(adenosine diphosphate-ribose) polymerase (PARP). Approval in December 2014 was based on a trial by Kaufman and colleagues that included patients with ovarian cancer and germline BRCA mutations. The final publication included 193 patients with a median of 4 prior regimens; all were considered platinum resistant or not suitable for further platinum therapy. Using single-agent olaparib, the response rate was 31% with a 225-day median duration of response. Generally, toxicities were mild to moderate and included fatigue, nausea and vomiting, and anemia. One concern about olaparib is the potentially increased rate of myelodysplastic syndrome and acute myeloid leukemia (2% in this trial).. H&O Are ...
Some experts believe that if ovarian or breast cancer runs in the family, women should be tested for genetic abnormalities. If first- or second-degree relatives have such cancers, particularly among Ashkenazi Jewish families, women should discuss genetic testing for BRCA abnormalities with their doctors. Women with certain BRCA gene mutations may be offered the option of having both ovaries and tubes removed after they no longer wish to bear children, even when no cancer is present. This approach eliminates the risk of ovarian cancer and reduces the risk of breast cancer. These women should be evaluated by a gynecologist who specializes in cancer (gynecologic oncologist). More information is available from the National Cancer Institute Cancer Information Service (1-800-4-CANCER) and the Womens Cancer Network (WCN) web site (www.wcn.org ...
Male breast cancer accounts for less than 1% of all breast cancers according to a study in 2003 by Weir et al. However, the time from onset of symptoms to diagnosis in men is longer than in women (approximately 22 months), and as a result, men often present with later-stage disease, most likely due to a lack of awareness that men can develop breast cancer. Genetically, while male BRCA1 mutation carriers have approximately a 1.2% risk of developing breast cancer, male BRCA2 mutation carriers have a 6.3% lifetime absolute risk of breast cancer. This is a 100-fold higher risk than exists in the general male population. In their article, Lucy R. Kahn, BSc (Hons) MB ChB MRCSEd, and J. Michael Dixon, BSc (Hons) MB ChB MD FRCS FRCSEd, discuss the case of a 43-year old man who presented in 2002 with a painless breast lump and a strong family history of breast cancer. The patient underwent surgery and endocrine therapy, followed by a regimen of 4 ...
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There are both genetic predisposition and behavioral risk factors for pancreatic cancer.. Genetic Predisposition. There is no identified familial form of pancreatic cancer but there is a genetic link in about 5% of patients. A mutation in the p16 tumor suppressor gene has been associated with increased risk. Alterations in BRCA-2, a breast cancer susceptibility gene have been identified in families with multiple cases of pancreatic cancer. The rates of pancreatic cancer are slightly higher in men than in women.67. Risk Factors. Age: most diagnoses are made between the ages of 60-80. Increased Body Mass Index (BMI): BMI is used to determine whether or not an individual is at a healthy weight. Overweight and obese people have higher BMI values. There is a correlation between increased BMI and pancreatic cancer.. Smoking: Pancreatic cancer rates in smokers are over twice that of non-smokers.. Diabetes: Abnormal ...
Part of the substantial unexplained familial aggregation of breast cancer may be due to interactions between common variants, but few studies have had adequate statistical power to detect interactions of realistic magnitude. We aimed to assess all two-way interactions in breast cancer susceptibility between 70 917 single nucleotide polymorphisms (SNPs) selected primarily based on prior evidence of a marginal effect. Thirty-eight international studies contributed data for 46 450 breast cancer cases and 42 461 controls of European origin as part of a multi-consortium project (COGS). First, SNPs were preselected based on evidence (P , 0.01) of a per-allele main effect, and all two-way combinations of those were evaluated by a per-allele (1 d.f.) test for interaction using logistic regression. Second, all 2.5 billion possible two-SNP combinations were evaluated using Boolean operation-based screening and testing, and SNP pairs with the strongest evidence of interaction (P , 10(-4)) were selected for ...
THURSDAY, Oct. 12, 2017 (HealthDay News) -- Breast cancer is the second leading cause of cancer death among women in the United States, and routine screenings remain the most reliable way to detect the disease early, a breast cancer expert says.. "Breast cancer can be treated more successfully if detected in its early phases, while it is small and has not yet spread," said Dr. Kathryn Evers, director of mammography at Fox Chase Cancer Center in Philadelphia. "With todays state-of-the-art treatment options and less extensive surgery, patients are experiencing better outcomes.". Older age is a leading risk factor for breast cancer. Most women are diagnosed after the age of 50. Having certain mutations in the BRCA1 and BRCA2 genes also predispose women to the disease. And there are some lifestyle-related risk factors that can be controlled, such as hormone therapy after menopause, obesity, alcohol intake and physical inactivity, Evers said.. ...
BACKGROUND: FANCM and RECQL have recently been reported as breast cancer susceptibility genes and it has been suggested that they should be included on gene panel tests for breast cancer predisposition. However, the clinical value of testing for mutations in RECQL and FANCM remains to be determined. In this study, we have characterised the spectrum of FANCM and RECQL mutations in women affected with breast or ovarian cancer from South-West Poland and West Ukraine. METHODS: We applied Hi-Plex, an amplicon-based enrichment method for targeted massively parallel sequencing, to screen the coding exons and proximal intron-exon junctions of FANCM and RECQL in germline DNA from unrelated women affected with breast cancer (n = 338) and ovarian cancer (n = 89) from Poland (n = 304) and Ukraine (n = 123 ...
Genetic Testing and Counseling. Women who meet certain criteria are encouraged to undergo BRACAnalysis genetic testing and counseling to find out if they carry the BRCA1 or BRCA2 breast cancer gene mutation. The staff at The Breast Center can help you determine whether or not you should have this genetic testing and provide counseling.. Breast Ultrasound. This procedure uses high-energy sound waves that bounce off internal tissues or organs to make echoes. The echoes form a picture of body tissue called a sonogram or ultrasonography.. A breast ultrasound procedure is commonly performed to determine if an abnormality detected by mammography or a palpable lump is a fluid-filled cyst or a solid tumor (benign or malignant). Breast ultrasound may also be used to identify masses in women whose breast tissue is too dense to be measured accurately by mammography. Breast ultrasound is generally not ...
|i|Background:|/i| Little is known about the preferences of at-risk Hispanic women to gain information on hereditary breast and ovarian cancer (HBOC). |i|Aims:|/i| This study s
Who should be screened for hereditary breast and ovarian cancer powerpoint presentation slides is available for free download uploaded in belonging ppt presentation Health & Wellness category, Download and Use!
Excerpt:. "Clinical data on the role of platinum salts in the treatment of triple-negative breast cancer (TNBC) - particularly germline (g) BRCA1-related TNBC - are encouraging in the neoadjuvant setting, where the pathologic complete response rate is improved with the addition of a platinum to anthracycline and taxane-based chemotherapy.. "Data have emerged to show the utility of incorporating platinums into the metastatic setting in TNBC as well, with the strongest evidence for use in patients who are BRCA1/2 mutation carriers or who express a BRCA-like genomic instability signature.". Go to full article.. ...
Copyright © 2020 BMJ Publishing Group Ltd, International Gynecologic Cancer Society, & European Society of Gynaecological Oncology. All rights reserved ...
... DNA Repair (Amst). 2019 Aug 30;82:102697 Authors: Rajkumar-Calkins AS, Szalat R, Dreze M, Khan I, Frazier Z, Reznichenkov E, Schnorenberg MR, Tsai YF, Nguyen H, Kochupurakkal B, DAndrea AD, Shapiro GI, Lazaro JB, Mouw KW Abstract Homologous recombination deficiency conferred by alterations in BRCA1 or BRCA2...
Pancreatic cancer remains one of the most lethal of malignancies and a major health burden. We performed whole-genome sequencing and copy number variation (CNV) analysis of 100 pancreatic ductal adenocarcinomas (PDACs). Chromosomal rearrangements leading to gene disruption were prevalent, affecting genes known to be important in pancreatic cancer (TP53, SMAD4, CDKN2A, ARID1A and ROBO2) and new candidate drivers of pancreatic carcinogenesis (KDM6A and PREX2). Patterns of structural variation (variation in chromosomal structure) classified PDACs into 4 subtypes with potential clinical utility: the subtypes were termed stable, locally rearranged, scattered and unstable. A significant proportion harboured focal amplifications, many of which contained druggable oncogenes (ERBB2, MET, FGFR1, CDK6, PIK3R3 and PIK3CA), but at low individual patient prevalence. Genomic instability co-segregated with inactivation of DNA maintenance ...

Key Pathways Identified in Triple-negative Breast Cancer - The ASCO PostKey Pathways Identified in Triple-negative Breast Cancer - The ASCO Post

Additionally, gene expression (mRNA) was measured for 450 genes.. They found amplifications, deletions, or mutations of known ... involved in signaling and cellular death), DNA repair genes (such as BRCA1 and BRCA2), Ras/MAP kinase (cellular proliferation, ... differentiation and death), cell-cycle genes, and growth factor receptors. Novel mutations of unknown significance could not be ... About 40% of patients with only one of these aberrations were alive at 6 years, but in cases where both genes were amplified, ...
more infohttps://www.ascopost.com/issues/february-1-2013/key-pathways-identified-in-triple-negative-breast-cancer/

Constitutional Genomic Instability with Inversions, Duplications, and Amplifications in 9p23-24 in BRCA2 Mutation Carriers |...Constitutional Genomic Instability with Inversions, Duplications, and Amplifications in 9p23-24 in BRCA2 Mutation Carriers |...

... as if BRCA2 acts as a tumor suppressor gene. Studies in mice in which the Brca2 gene has been homozygously mutated with the ... Mutant BRCA2 genes often encode truncated BRCA2 proteins apparently unable to assume a nuclear localization (12) , and a range ... from BRCA2-linked pedigrees 1, 2, and 3 (Figs. 1 ⇓ 2 ⇓ 3) ⇓ . Additionally, blood samples were collected from three cancer-free ... First, homozygous alteration of distal 9p could be a lethal factor on the cellular level. Second, damage of one 9p allele could ...
more infohttp://cancerres.aacrjournals.org/content/61/13/5179

Discovery - BRCA Connection to Breast and Ovarian Cancer - National Cancer InstituteDiscovery - BRCA Connection to Breast and Ovarian Cancer - National Cancer Institute

NCI-funded research helped identify inherited BRCA1 and BRCA2 genetic mutations and their connection to breast and ovarian ... BRCA1 and BRCA2 mutations can lead to cancer. Both BRCA1 and BRCA2 belong to a class of genes known as tumor suppressor genes ... helped to identify inherited BRCA1 and BRCA2 harmful gene mutations and to develop a screening test for these mutations in ... Additionally, interpreting the results of genetic tests, including BRCA1 and BRCA2 mutations, is not always straightforward. ...
more infohttps://www.cancer.gov/research/progress/discovery/brca

Frontiers | Mechanisms and insights into drug resistance in cancer | PharmacologyFrontiers | Mechanisms and insights into drug resistance in cancer | Pharmacology

... mutation and amplification of drug targets, as well as genetic rewiring which can lead to impaired apoptosis. Tumor ... mutation and amplification of drug targets, as well as genetic rewiring which can lead to impaired apoptosis. Tumor ... is seen in breast and ovarian cancers carrying mutations in the BRCA1 and BRCA2 genes, important mediators of DNA double-strand ... 2006). Presence of epidermal growth factor receptor gene T790M mutation as a minor clone in non-small cell lung cancer. Cancer ...
more infohttps://www.frontiersin.org/articles/10.3389/fphar.2013.00028/full

Diagnostics  | Free Full-Text | Hepatocellular Carcinoma, Fibrolamellar Variant: Diagnostic Pathologic Criteria and Molecular...Diagnostics | Free Full-Text | Hepatocellular Carcinoma, Fibrolamellar Variant: Diagnostic Pathologic Criteria and Molecular...

Other mutations in BRCA2 gene (~1/20 of cases) may also occur. There is an 8-gene signature, which has been identified as ... additionally, immunohistochemistry (IHC). Remarkably, all three classes show expression of genes that regulate neuroendocrine ... which are involved in specific cellular functions, including individual cell growth, cell proliferation and differentiation, ... Allegra, C.J.; Rumble, R.B.; Hamilton, S.R.; Mangu, P.B.; Roach, N.; Hantel, A.; Schilsky, R.L. Extended RAS gene mutation ...
more infohttp://www.mdpi.com/2075-4418/6/1/3/htm

Toshiyasu Taniguchi - Searle Scholars ProgramToshiyasu Taniguchi - Searle Scholars Program

... and 9 FA genes (FANCA, B, C, D1(BRCA2), D2, E, F, G, and L) have been identified. The breast/ovarian cancer susceptibility gene ... For example, mutations in p53, Rb, and ATM genes are responsible for the genetic diseases, Li-Fraumeni syndrome, familial ... products (BRCA1 and BRCA2 proteins) and all of the FA proteins cooperate in a common pathway required for the cellular ... Additionally, the Fanconi anemia pathway is an attractive model system for studying cancer, DNA repair and ubiquitin biology. ...
more infohttps://www.searlescholars.net/people/toshiyasu-taniguchi

The Fanconi anemia pathway and ubiquitin | BMC Biochemistry | Full TextThe Fanconi anemia pathway and ubiquitin | BMC Biochemistry | Full Text

All these factors are required for cellular resistance to DNA crosslinking agents. The inactivation of the FA pathway has also ... To date, 12 FA gene products have been identified, which cooperate in a common DNA damage-activated signaling pathway ... Monoubiquitylated FANCD2 colocalizes in nuclear foci with proteins involved in DNA repair, including BRCA1, FANCD1/BRCA2, FANCN ... cancer/leukemia susceptibility and cellular hypersensitivity to DNA crosslinking agents, such as cisplatin. ...
more infohttps://bmcbiochem.biomedcentral.com/articles/10.1186/1471-2091-8-S1-S10

PALB2 (partner and localizer of BRCA2)PALB2 (partner and localizer of BRCA2)

... partner and localizer of BRCA2), Authors: Helmut Hanenberg and Paul R. Andreassen. Published in: Atlas Genet Cytogenet Oncol ... PALB2 [ Somatic mutations - Copy number]. Cancer Gene: Census. PALB2 Somatic Mutations in Cancer : COSMIC. PALB2 [overview] [ ... Also, heterozygous germ-line mutations of PALB2, like mutations in several other essential HR genes listed above, yield an ... As a mediator of HR, PALB2 recruits BRCA2 and the RAD51 recombinase to sites of DNA damage (Xia et al., 2006). Additionally, ...
more infohttp://atlasgeneticsoncology.org/Genes/GC_PALB2.html

PALB2 (partner and localizer of BRCA2)PALB2 (partner and localizer of BRCA2)

... partner and localizer of BRCA2), Authors: Helmut Hanenberg and Paul R. Andreassen. Published in: Atlas Genet Cytogenet Oncol ... PALB2(select the gene name). Impact of mutations. [PolyPhen2] [Provean] [Buck Institute : MutDB] [Mutation Assessor] [ ... Also, heterozygous germ-line mutations of PALB2, like mutations in several other essential HR genes listed above, yield an ... As a mediator of HR, PALB2 recruits BRCA2 and the RAD51 recombinase to sites of DNA damage (Xia et al., 2006). Additionally, ...
more infohttp://atlasgeneticsoncology.org/Genes/PALB2ID46402ch16p12.html

Protocols and Video Articles Authored by Elizabeth Jaffee (Translated to Norwegian)Protocols and Video Articles Authored by Elizabeth Jaffee (Translated to Norwegian)

SMAD4 Gene Mutations Are Associated with Poor Prognosis in Pancreatic Cancer Clinical Cancer Research : an Official Journal of ... Two prominent clusters of genes were related to the high rates of cellular proliferation in pancreatic cancer cell lines and ... Additionally, T cells can continue to proliferate in response to immunogenic proteins expressed in cancer until all the tumour ... and the PALB2 protein is a binding partner for BRCA2. These results illustrate that complete, unbiased sequencing of protein- ...
more infohttps://www.jove.com/author/Elizabeth_Jaffee?language=Norwegian

Poly (ADP-Ribose) Polymerase as a Novel Therapeutic Target in Cancer | Clinical Cancer ResearchPoly (ADP-Ribose) Polymerase as a Novel Therapeutic Target in Cancer | Clinical Cancer Research

Mutations in PALB2 have been linked to hereditary breast cancers not associated with mutations in BRCA genes (22). Additionally ... The BRCA2-mutated cancers and the sporadic GII-high-III cases were predominantly luminal in gene expression, whereas the BRCA1- ... Activation of these DNA repair mechanisms triggers cellular signaling pathways that block gene transcription, arrest the cell ... ATM may account for up to 3% of familial breast cancers that do not have mutations in the BRCA1/2 genes (22). ATM functions in ...
more infohttp://clincancerres.aacrjournals.org/content/16/18/4517?ijkey=bf199cc2237c9b41cf2d28887ec0cf83b29c68a1&keytype2=tf_ipsecsha

Gadd45a: An Elusive Yet Attractive Candidate Gene in Pancreatic Cancer | Clinical Cancer ResearchGadd45a: An Elusive Yet Attractive Candidate Gene in Pancreatic Cancer | Clinical Cancer Research

Additionally, because Gadd45a is a p53 effector gene, mutations in Tp53 can certainly contribute to altering Gadd45a expression ... tumor suppressor genes (p16, p53, DPC, BRCA2, p300, MKK4, TGF-β1, TGF-β2, and so forth), or DNA repair genes [hMLH1 and hMSH2 ( ... Small alterations in the relative amounts of Gadd45a protein in different cellular compartments could have detrimental effects ... The relatively high mutation frequency in exon 4 of Gadd45a creates the need for a better understanding of this gene and to ...
more infohttp://clincancerres.aacrjournals.org/content/8/8/2475

Non-coding RNA - WikipediaNon-coding RNA - Wikipedia

In higher eukaryotes microRNAs regulate gene expression. A single miRNA can reduce the expression levels of hundreds of genes. ... these patients were noncarriers of BRCA1 or BRCA2 mutations, lending the possibility that familial breast cancer may be caused ... Additionally artificially evolved RNAs also fall under the fRNA umbrella term. Some publications state that ncRNA and fRNA are ... These range from ncRNAs of central importance that are conserved across all or most cellular life through to more transient ...
more infohttps://en.wikipedia.org/wiki/Non-coding_RNA

Hereditary breast and ovarian cancer susceptibility genes (Review)Hereditary breast and ovarian cancer susceptibility genes (Review)

... mutation in BRCA2 (13). BRCA gene founder mutations such as BRCA1c. 5266dup mutation, BRCA2999del5 mutation and BRCA1delexon17 ... BRCA1 and BRCA2 maintain cellular events associated with the genomic integrity. Mutations that affect the mechanisms involved ... Each gene was also linked to NCBI Entrez Gene pages (http://www.ncbi.nlm.nih.gov/sites/entrez). Additionally, references in ... Up to 80% of the HBOC cases are due to mutations in BRCA1 or BRCA2 genes. Both BRCA1 and BRCA2 mutations are scattered ...
more infohttps://www.spandidos-publications.com/or/30/3/1019

Genome Integrity Discussion Group Meeting (3) | The New York Academy of SciencesGenome Integrity Discussion Group Meeting (3) | The New York Academy of Sciences

Mutations in multiple genes involved in HDR are linked to breast cancer susceptibility including BRCA1 and BRCA2. The mammary ... A common type of gross chromosomal rearrangement (GCR) is gene amplification, an increase in gene copy number. Duplicated ... Additionally, we replace endogenous 53BP1 with wild type or a mutant form with reduced gH2AX affinity and investigate the ... modifications on histone tails can regulate the localization of chromatin-associated proteins implicated in essential cellular ...
more infohttps://www.nyas.org/events/2015/genome-integrity-discussion-group-meeting-3/

Distinct functions of BRCA1 and BRCA2 in double-strand break repair | Breast Cancer Research | Full TextDistinct functions of BRCA1 and BRCA2 in double-strand break repair | Breast Cancer Research | Full Text

We discuss the interaction of BRCA1 with the BACH1 and BARD1 proteins, and suggest that the pleiotropic nature of mutations in ... The BRCA1 and BRCA2 proteins are required for homologous recombination and DNA break repair, leading to the suggestion that ... In contrast, the role of BRCA2 in DNA repair may be more defined by its direct interaction with the RAD51 recombinase. ... However, direct evidence of a stable BRCA1/BRCA2 complex has not been demonstrated. Rather, the two proteins have been found as ...
more infohttps://breast-cancer-research.biomedcentral.com/articles/10.1186/bcr417

Antigenic variation - WikipediaAntigenic variation - Wikipedia

... brucei BRCA2 gene with RAD51 (however, this is not the only responsible mechanism, as BRCA2 variants still display some VSG ... Switching of VSG proteins occurs at a rate substantially higher than the background mutation rate of other genes in the ... Additionally amino acid co-evolution is a challenging issue that needs to be addressed. For example, a substitution in a ... as well as cellular components of the innate and adaptive immune systems. In order to protect itself from host defenses, the ...
more infohttps://en.wikipedia.org/wiki/Antigenic_variation

Breast Cancer: Symptoms, Causes, Treatment, Information & SupportBreast Cancer: Symptoms, Causes, Treatment, Information & Support

BRCA Genes and Your Breast Cancer Risk. BRCA, known as the "breast cancer gene," is one of several genetic mutations ( ... Changes in two genes, known as BRCA1 and BRCA2 (short for breast cancer 1 and breast cancer 2), can be inherited and lead to a ... Additionally, removal of the ovaries has shown to reduce the risk of developing breast cancer in women who have the BRCA1 or ... Targeted therapy is a type of treatment that has been developed to directly work against some of the cellular changes that have ...
more infohttps://www.emedicinehealth.com/breast_cancer/article_em.htm

XRCC2 (X-ray repair cross complementing 2)XRCC2 (X-ray repair cross complementing 2)

Mutation of the RAD51C gene in a Fanconi anemia-like disorder. Vaz F, Hanenberg H, Schuster B, Barker K, Wiek C, Erven V, ... similar to other late FA genes such as BRCA1, BRCA2, PALB2 and RAD51C (Park et al., 2012). However, subsequent studies could ... In a screen for X-ray sensitive cellular mutants in Chinese hamster ovary (CHO) cells, the irs1 clone, which was thought to be ... Additionally, EZH2, a subunit of the PRC2 transcriptional repressor complex, may have a role in downregulating XRCC2 expression ...
more infohttp://www.atlasgeneticsoncology.org/Genes/XRCC2ID334ch7q36.html

New insights into the generation and role of de novo mutations in health and disease | Genome Biology | Full TextNew insights into the generation and role of de novo mutations in health and disease | Genome Biology | Full Text

De novo mutations have been shown to be a major cause of severe early-onset genetic disorders such as intellectual disability, ... Recent studies have also shown that de novo mutations are predominantly of paternal origin and that their number increases with ... In fact, the occurrence of novel mutations in each generation explains why these reproductively lethal disorders continue to ... Here, we review the recent literature on de novo mutations, covering their detection, biological characterization, and medical ...
more infohttps://genomebiology.biomedcentral.com/articles/10.1186/s13059-016-1110-1

Plus itPlus it

... and cellular sensitivity to DNA cross-linking agents (Fanconi, 1967; Kee and DAndrea, 2012). So far, mutations in 19 genes ... In addition, mutation of the QUARTET1 gene enables tetrad analysis because the four pollen grains originating from each meiotic ... Additionally, FANCD2 may serve as a scaffold for several other nucleases like XPF-ERCC1 and MUS81-EME1 via recruitment of SLX4 ... and BRCA2 (FANCD1) (reviewed in Jacquemont and Taniguchi, 2007). In addition, FANCD2 is phosphorylated by the kinase ATM ( ...
more infohttp://www.plantcell.org/content/30/2/415

Plus itPlus it

... including heritable breast cancers with BRCA2 mutations (22-24). It has been shown that Smad3 and BRCA2 can synergize to affect ... BRCA2 and Smad3 synergize in regulation of gene transcription. Oncogene 2002;21:5660-4. ... Expression of Smad3-regulated genes in study cell lines. MCF7 (A) and T47D (B) cell lines were transfected with WT Smad3 or the ... Cellular lysates were spun, supernatants were recovered, and the total protein concentration was determined by protein assay ( ...
more infohttps://mcr.aacrjournals.org/content/8/10/1375

WGC2010WGC2010

... and pegylated liposomal doxorubicin in patients with BRCA1 or BRCA2 muta- tions and intermittent ovarian cancer. Soups should ... PCR and gene sequencing, over 110 polymorphisms were subsequently identified in the CYP2D6 gene. These recommenda- tions forth ... The HSP70 genes of divers subfamilies were initially characterized as nearest in ten tandemly repeated copies in the genome ( ... Additionally, there was no statistical content demonstrated in terms of duplication UTI within 1 to 15 months after the primary ...
more infohttp://www.wgc2010.sk/index.php/en/messageboard/1397

POLL | Cancer Genetics WebPOLL | Cancer Genetics Web

... of hereditary breast cancer has been accounted for by mutations in known genes. Most of these genes, such as BRCA1, BRCA2, TP53 ... The BRCA1 gene product helps to maintain genomic integrity through its participation in the cellular response to DNA damage: ... Additionally, these PNPs contain (1) PLGA conjugated to polyethylene glycol (PEG) for enhanced pharmacokinetics of the ... The overall mutation prevalence was 1.1% (0.5% for BRCA1 and 0.6% for BRCA2). Among the 22 mutation carriers, the mean estimate ...
more infohttp://www.cancerindex.org/geneweb/POLL.htm

Methylation and protein expression of DNA repair genes: association with chemotherapy exposure and survival in sporadic ovarian...Methylation and protein expression of DNA repair genes: association with chemotherapy exposure and survival in sporadic ovarian...

Restoration of BRCA1 and BRCA2 mediates resistance to platinum chemotherapy in recurrent BRCA1 and BRCA2 mutated hereditary ... Additionally, we assessed whether promoter methylation of BRCA1, MLH1 or FANCF influenced response to chemotherapy or explained ... We evaluated BRCA1, BRCA2, and MLH1 protein expression in 115 sporadic primary ovarian carcinomas, of which 31 had paired ... BRCA1 and BRCA2 protein expression were highly concordant (p , 0.0001). MLH1 protein loss occurred in 28/115 (24%) primary ...
more infohttps://molecular-cancer.biomedcentral.com/articles/10.1186/1476-4598-8-48
  • They found amplifications, deletions, or mutations of known or implied functional significance in about two dozen genes, and approximately 90% of all patients had at least one aberration in pathways related to P13K/mTOR (involved in signaling and cellular death), DNA repair genes (such as BRCA1 and BRCA2 ), Ras/MAP kinase (cellular proliferation, differentiation and death), cell-cycle genes, and growth factor receptors. (ascopost.com)
  • TGFβ/activin signaling is transduced through receptor-mediated phosphorylation of intracellular Smad2 and Smad3, which form a complex with Smad4, translocate to the nucleus, and, along with coactivators and cell-specific DNA-binding factors, regulate target gene expression relevant to several aspects of cell growth and differentiation ( 3 - 5 ). (aacrjournals.org)
  • DNA repair genes critically regulate the cellular response to chemotherapy and epigenetic regulation of these genes may be influenced by chemotherapy exposure. (biomedcentral.com)
  • The fact that mutations in either Tp53 or ATM genes in cancer-prone ataxia-telangiectasia patients result in decreased Gadd45a expression after IR 2 draws an interesting correlation between Gadd45a and cancer. (aacrjournals.org)
  • The apparent lack of an increased cancer risk in Brca2 +/− mice (10) , a setting that would reflect the situation in humans, clearly testifies to this problem. (aacrjournals.org)
  • 1987). Two groups subsequently mapped the region containing the defective gene to 7q36.1 in humans based on somatic cell hybrids capable of complementing the hypersensitivity of irs1 cells to the DNA interstrand crosslinking agent mitomycin C (MMC) (Jones et al. (atlasgeneticsoncology.org)
  • There is a long-standing interest in the study of the frequency and characteristics of de novo mutations in humans, as these are crucial to the evolution of our species and play an important role in disease. (biomedcentral.com)
  • DNA sustains damage through exposure to chemicals, UV light, ionizing radiation, chemotherapy, or products of cellular and oxidative metabolism ( 1 ). (aacrjournals.org)
  • Additionally, we assessed whether promoter methylation of BRCA1, MLH1 or FANCF influenced response to chemotherapy or explained alterations in protein expression after chemotherapy exposure. (biomedcentral.com)
  • Genetic studies conducted in BRCA1 - and BRCA2 -defective cell lines [ 7 , 9 , 10 ] have further revealed that these tumour suppressor genes are required for maintenance of genome integrity and for normal levels of resistance to DNA damage. (biomedcentral.com)
  • Recent genome and exome sequencing studies of parent-offspring trios have provided the first insights into the number and distribution of these de novo mutations in health and disease, pointing to risk factors that increase their number in the offspring. (biomedcentral.com)
  • The HSP70 genes of divers subfamilies were initially characterized as nearest in ten tandemly repeated copies in the genome (Requena et al. (wgc2010.sk)
  • Researchers then identified the BRCA1 gene within this region, which established a clear association between inheriting the mutant forms of the gene (known as germline mutations ) with increased cases of cancer. (cancer.gov)
  • (4) identified Gadd45a (a growth arrest and DNA damage-inducible gene) as a new factor in the development of pancreatic cancer. (aacrjournals.org)
  • Mutations in exon IV are within the COOH-terminal oligomerization subdomain and PCNA binding regions (residues 141-159). (aacrjournals.org)
  • Several studies have shown that BRCA1 and BRCA2 testing and risk assessment can be integrated into primary care. (cancer.gov)