Li-Fraumeni Syndrome: Rare autosomal dominant syndrome characterized by mesenchymal and epithelial neoplasms at multiple sites. MUTATION of the p53 tumor suppressor gene, a component of the DNA DAMAGE response pathway, apparently predisposes family members who inherit it to develop certain cancers. The spectrum of cancers in the syndrome was shown to include, in addition to BREAST CANCER and soft tissue sarcomas (SARCOMA); BRAIN TUMORS; OSTEOSARCOMA; LEUKEMIA; and ADRENOCORTICAL CARCINOMA.Genes, p53: Tumor suppressor genes located on the short arm of human chromosome 17 and coding for the phosphoprotein p53.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.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.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.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.Syndrome: A characteristic symptom complex.Choroid Plexus Neoplasms: Benign or malignant tumors which arise from the choroid plexus of the ventricles of the brain. Papillomas (see PAPILLOMA, CHOROID PLEXUS) and carcinomas are the most common histologic subtypes, and tend to seed throughout the ventricular and subarachnoid spaces. Clinical features include headaches, ataxia and alterations of consciousness, primarily resulting from associated HYDROCEPHALUS. (From Devita et al., Cancer: Principles and Practice of Oncology, 5th ed, p2072; J Neurosurg 1998 Mar;88(3):521-8)Adrenal Cortex Neoplasms: Tumors or cancers of the ADRENAL CORTEX.Heterozygote: An individual having different alleles at one or more loci regarding a specific character.Checkpoint Kinase 2: Enzyme activated in response to DNA DAMAGE involved in cell cycle arrest. The gene is located on the long (q) arm of chromosome 22 at position 12.1. In humans it is encoded by the CHEK2 gene.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.Genetic Predisposition to Disease: A latent susceptibility to disease at the genetic level, which may be activated under certain conditions.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.Proto-Oncogene Proteins c-mdm2: An E3 UBIQUITIN LIGASE that interacts with and inhibits TUMOR SUPPRESSOR PROTEIN P53. Its ability to ubiquitinate p53 is regulated by TUMOR SUPPRESSOR PROTEIN P14ARF.Fibroblasts: Connective tissue cells which secrete an extracellular matrix rich in collagen and other macromolecules.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.Neoplasms: New abnormal growth of tissue. Malignant neoplasms show a greater degree of anaplasia and have the properties of invasion and metastasis, compared to benign neoplasms.DNA Mutational Analysis: Biochemical identification of mutational changes in a nucleotide sequence.

*  LongevityMap variant
... including hereditary cancers such as Li-Fraumeni syndrome. Alternative splicing of this gene and the use of alternate promoters ...
  http://genomics.senescence.info/longevity/entry.php?id=G293
*  Immortal, telomerase-negative cell lines derived from a Li-Fraumeni syndrome patient exhibit telomere length variability and...
Five immortal cell lines derived from a Li-Fraumeni syndrome patient (MDAH 087) with a germline mutant p53 allele were ... Five immortal cell lines derived from a Li-Fraumeni syndrome patient (MDAH 087) with a germline mutant p53 allele were ... Li-Fraumeni syndrome; PD, population doubling; TRAP, telomeric repeat amplification protocol; TRF, terminal restriction ...
  http://oxfordindex.oup.com/view/10.1093/carcin/bgg024
*  Abstract B10: Factors predicting decisional conflict and p53 genetic testing intention among those at risk of Li-Fraumeni...
Background: Li-Fraumeni syndrome (LFS) is a rare genetic condition that increases lifetime risk for a variety of cancers in ... Factors predicting decisional conflict and p53 genetic testing intention among those at risk of Li-Fraumeni syndrome. Shelly R. ... Factors predicting decisional conflict and p53 genetic testing intention among those at risk of Li-Fraumeni syndrome ... Factors predicting decisional conflict and p53 genetic testing intention among those at risk of Li-Fraumeni syndrome ...
  http://cancerpreventionresearch.aacrjournals.org/content/4/10_Supplement/B10
*  Li-Fraumeni Syndrome
... is an autosomal-dominant familial cancer syndrome that results in an increased ... Chompret A. The Li-Fraumeni syndrome. Biochimie. 2002 Jan;84(1):75-82. *Malkin D. Li-fraumeni syndrome. Genes Cancer. 2011 Apr; ... and relatives of patients with Li-Fraumeni syndrome. Regarding the patient with Li-Fraumeni syndrome and a known malignancy: ... A Li-Fraumeni syndrome spectrum tumor before age 46 years.] AND [At least one first- or second-degree relative with a Li- ...
  https://roentgenrayreader.blogspot.com/2011/12/li-fraumeni-syndrome.html
*  Cancer Treatment Could Come From Link to Childhood Leukemia
Researchers found that more than one-third of patients with hypodiploid ALL also have Li-Fraumeni syndrome, an inherited ...
  https://www.webpronews.com/cancer-treatment-could-come-from-link-to-childhood-leukemia-2013-01/
*  RT² qPCR Primer Assay for Human TP53
... but also as germline mutations in some cancer-prone families with Li-Fraumeni syndrome. ...
  http://www.sabiosciences.com/primerinfo.php?pcatn=PPH00213A
*  Dana-Farber/Children's Hospital Cancer Center experts recommend genetic counseling for pediatric sarcoma patients - Healthcanal...
Li-Fraumeni syndrome was first described in 1969 by Dana-Farber physician-scientist Frederick Li, MD, and his mentor, Joseph F ... a finding that made genetic testing for Li-Fraumeni syndrome possible.. Cancers typically diagnosed in patients with Li- ... The information may also be helpful for adults with Li-Fraumeni syndrome who are already being treated for cancer. Garber is ... The goal is to learn how to find cancers early and treat them effectively in people with Li-Fraumeni syndrome. ...
  https://www.healthcanal.com/cancers/26418-dana-farberchildrens-hospital-cancer-center-experts-recommend-genetic-counseling-for-pediatric-sarcoma-patients.html
*  Tumors of LFS family show impaired TP53 transcriptionRN | Open-i
TP53 intron 1 hotspot rearrangements are specific to sporadic osteosarcoma and can cause Li-Fraumeni syndrome. ... TP53 intron 1 hotspot rearrangements are specific to sporadic osteosarcoma and can cause Li-Fraumeni syndrome. ... can cause Li-Fraumeni syndrome (LFS). Recently, recurrent genomic rearrangements in intron 1 of TP53 have been described in ... can cause Li-Fraumeni syndrome (LFS). Recently, recurrent genomic rearrangements in intron 1 of TP53 have been described in ...
  https://openi.nlm.nih.gov/detailedresult.php?img=PMC4480712_oncotarget-06-7727-g005&req=4
*  Cancer Epidemiology and Prevention - David Schottenfeld; Joseph F. Fraumeni - Oxford University Press
Hereditary Neoplastic Syndromes, Noralane M. Lindor, Carl J. Lindor, and Mark H. Greene. 29. Genetic Modifiers of Cancer Risk, ... Esophageal Cancer, William J. Blot, Joseph K. McLaughlin, and Joseph F. Fraumeni, Jr.. 37. Stomach Cancer, Atsuko Shibata and ... Biliary Tract Cancer, Ann W. Hsing, Asif Rashid, Susan S. Devesa, and Joseph F. Fraumeni, Jr.. 41. Cancers of the Small ... Edited by David Schottenfeld and Joseph F. Fraumeni, Jr.. This volume provides the most authoritative account of cancer causes ...
  https://global.oup.com/academic/product/cancer-epidemiology-and-prevention-9780195149616?facet_narrowbybinding_facet=Ebook&lang=en&cc=us
*  Li-Fraumeni syndrome - Wikipedia
Li-Fraumeni Syndrome by Katherine A Schneider and Frederick Li, in GeneReviews, a section of GeneTests, published online by the ... Fraumeni, J. F. (1998). "Multiple Primary Cancers in Families With Li-Fraumeni Syndrome". Journal of the National Cancer ... Rapp-Hodgkin syndrome/Hay-Wells syndrome/Ectrodactyly-ectodermal dysplasia-cleft syndrome 3/Limb-mammary syndrome/OFC8 ... a Li-Fraumeni syndrome p53 mutation. Erratum for "Germ Line p53 Mutations in a Familial Syndrome of Breast Cancer, Sarcomas, ...
  https://en.wikipedia.org/wiki/Li-Fraumeni_syndrome
*  NewYork-Presbyterian Queens - Li-Fraumeni Syndrome
Li-Fraumeni Syndrome. The risk for breast cancer and many other forms of cancer is increased with Li-Fraumeni syndrome (LFS), a ... genetic autosomal dominant cancer syndrome. A diagnosis of LFS is made when all of the following characteristics are present in ...
  http://www.nyhq.org/diw/content.asp?PageID=P08127&More=WTN
*  Li-Fraumeni syndrome - Wikipedia
Li-Fraumeni syndrome, in the National Library of Medicine Genetics Home Reference (an introduction to the disease) Li-Fraumeni ... a Li-Fraumeni syndrome p53 mutation. Erratum for "Germ Line p53 Mutations in a Familial Syndrome of Breast Cancer, Sarcomas, ... Fraumeni, J. F. (1998). "Multiple Primary Cancers in Families With Li-Fraumeni Syndrome". Journal of the National Cancer ... Li-Fraumeni syndrome is diagnosed if the following three criteria are met: the patient has been diagnosed with a sarcoma at a ...
  https://en.wikipedia.org/wiki/Li%E2%80%93Fraumeni_syndrome
*  Contribution of de novo and mosaic TP53 mutations to Li-Fraumeni syndrome | Journal of Medical Genetics
Contribution of de novo and mosaic TP53 mutations to Li-Fraumeni syndrome ... Contribution of de novo and mosaic TP53 mutations to Li-Fraumeni syndrome ... Contribution of de novo and mosaic TP53 mutations to Li-Fraumeni syndrome ...
  http://jmg.bmj.com/content/early/2017/10/25/jmedgenet-2017-104976.share
*  TP53 germline mutation testing in 180 families suspected of Li-Fraumeni syndrome: mutation detection rate and relative...
Background Li-Fraumeni syndrome (LFS) is a rare autosomal dominant cancer predisposition syndrome. Most families fulfilling the ... TP53 germline mutation testing in 180 families suspected of Li-Fraumeni syndrome: mutation detection rate and relative ... Li-Fraumeni-like (LFL) and Chompret criteria. We investigated which criteria for TP53 mutation analysis resulted in the highest ...
  http://dare.uva.nl/search?metis.record.id=341071
*  Li-Fraumeni Syndrome 2
Build: Sat Feb 17 08:59:16 EST 2018 (commit: 16064c5). National Center for Advancing Translational Sciences (NCATS), 6701 Democracy Boulevard, Bethesda MD 20892-4874 • 301-435-0888. ...
  https://pharos.nih.gov/idg/diseases/Li-Fraumeni%20Syndrome%202
*  Li-Fraumeni Syndrome Genetic Testing - Clinician - Ambry Genetics
Li-Fraumeni Syndrome. Li-Fraumeni syndrome is a highly penetrant, yet rare, condition that predisposes to many tumors. Tumors ... Part II: Marfan Syndrome and the Unknowns of Genetic Testing. *Feb 21, 2018 ...
  http://www.ambrygen.com/clinician/genetic-testing/81/neurology/li-fraumeni-syndrome
*  Radiation Oncology/Cancer Syndromes/Li-Fraumeni - Wikibooks, open books for an open world
Li-Fraumeni Syndrome[edit]. *Gene Clinics Entry. *Originally published by Li & Fraumeni in 1969 *6 component tumors inherited ... Classically associated with Li Fraumeni syndrome; approximately 50% of Li Fraumeni patients have p53 mutation ... Li-Fraumeni-like Syndrome (LFL) criteria: *A proband with any childhood cancer or sarcoma, brain tumor, or adrenal cortical ... Classic Li-Fraumeni Syndrome (LFS) criteria: *A proband with a sarcoma diagnosed before 45 years of age AND ...
  https://en.wikibooks.org/wiki/Radiation_Oncology/Cancer_Syndromes/Li-Fraumeni
*  Autism spectrum disorder and Li-Fraumeni syndrome: purely coincidental or mechanistically associated? | Molecular and Cellular...
Li-Fraumeni syndrome, resulting from germline mutations in the TP53 gene, represents a well-known cancer susceptibility ... Autism spectrum disorderLi-Fraumeni syndromeHypodiploid leukemia. Findings. Autism spectrum disorder (ASD) is a group of ... Autism spectrum disorder and Li-Fraumeni syndrome: purely coincidental or mechanistically associated?. ... the diagnosis of Li-Fraumeni syndrome (LFS, OMIM #151623) was made. The boy was treated according to the high-risk protocol of ...
  https://molcellped.springeropen.com/articles/10.1186/s40348-017-0075-9
*  Risk factors for adrenal gland cancer - Canadian Cancer Society
Li-Fraumeni syndrome. Li-Fraumeni syndrome increases the risk of developing several different types of cancer, including ... Beckwith-Wiedemann syndrome. Beckwith-Wiedemann syndrome affects how different parts of the body grow. It increases the risk of ... Von Hippel-Lindau (VHL) syndrome VHL syndrome affects blood vessels in the eyes, brain, spinal cord, adrenal glands or other ...
  http://www.cancer.ca/en/cancer-information/cancer-type/adrenal-gland/risks/?region=mb
*  TP53 gene - Genetics Home Reference
Li-Fraumeni syndrome appears to be the only cancer syndrome associated with inherited mutations in this gene. This condition ... as part of a rare cancer syndrome called Li-Fraumeni syndrome (described below). These mutations are thought to account for ... Many of the mutations associated with Li-Fraumeni syndrome change single amino acids in the part of the p53 protein that binds ... Schneider K, Zelley K, Nichols KE, Garber J. Li-Fraumeni Syndrome. 1999 Jan 19 [updated 2013 Apr 11]. In: Pagon RA, Adam MP, ...
  https://ghr.nlm.nih.gov/gene/TP53
*  Family Cancer Syndromes
Li-Fraumeni syndrome. Li-Fraumeni syndrome is a rare inherited syndrome that can lead to the development of a number of cancers ... Hisada M, Garber JE, Fung CY, Fraumeni JF Jr, Li FP. Multiple primary cancers in families with Li-Fraumeni syndrome. J Natl ... Li-Fraumeni syndrome can also be caused by mutations in a tumor suppressor gene called CHEK2, which also normally helps stop ... If someone has Li-Fraumeni syndrome, their close relatives (especially children) have an increased chance of having a mutation ...
  https://www.cancer.org/cancer/cancer-causes/genetics/family-cancer-syndromes.html
*  Pathology High Yield (FA) Flashcards - Cram.com
Li-Fraumeni syndrome tumor suppresor gene:. p16. - chromosome. - associated tumor 9p. melanoma ... Plummer-Vinson syndrome. - atrophic glossitis. - esophageal webs - anemia (due to Fe deficiency) ...
  http://www.cram.com/flashcards/pathology-high-yield-fa-478727
*  Diseases - PrimePCR | Life Science | Bio-Rad
Li-Fraumeni syndrome. *Lipid metabolism - Inborn errors. *Marfan syndrome. *Melas syndrome. *Mental disorders diagnosed in ...
  http://www.bio-rad.com/en-us/prime-pcr-assays/pathway/diseases

Li–Fraumeni syndromeGermline STAT 1 Mutation: Interferons induce the formation of two transcriptional activators: gamma-activating factor (GAF) and interferon-stimulated gamma factor 3 (ISGF3). A natural heterozygous germline STAT1 mutation associated with susceptibility to mycobacterial but not viral disease was found in two unrelated patients with unexplained mycobacterial disease.P53: Tumor protein p53, also known as p53, cellular tumor antigen p53 (UniProt name), phosphoprotein p53, tumor suppressor p53, antigen NY-CO-13, or transformation-related protein 53 (TRP53), is any isoform of a protein encoded by homologous genes in various organisms, such as TP53 (humans) and Trp53 (mice). This homolog (originally thought to be, and often spoken of as, a single protein) is crucial in multicellular organisms, where it prevents cancer formation, thus, functions as a tumor suppressor.Pedigree chart: A pedigree chart is a diagram that shows the occurrence and appearance or phenotypes of a particular gene or organism and its ancestors from one generation to the next,pedigree chart Genealogy Glossary - About.com, a part of The New York Times Company.Malformative syndrome: A malformative syndrome (or malformation syndrome) is a recognizable pattern of congenital anomalies that are known or thought to be causally related (VIIth International Congress on Human Genetics).Silent mutation: Silent mutations are mutations in DNA that do not significantly alter the phenotype of the organism in which they occur. Silent mutations can occur in non-coding regions (outside of genes or within introns), or they may occur within exons.Dermal fibroblast: Dermal fibroblasts are cells within the dermis layer of skin which are responsible for generating connective tissue and allowing the skin to recover from injury. Using organelles (particularly the rough endoplasmic reticulum), dermal fibroblasts generate and maintain the connective tissue which unites separate cell layers.Loss of heterozygosity: Loss of heterozygosity (LOH) is a gross chromosomal event that results in loss of the entire gene and the surrounding chromosomal region.[Association of the autoimmune diseases scleroderma with an immunologic response to cancer,] Christine G.

(1/153) Radiation-induced G1 arrest is not defective in fibroblasts from Li-Fraumeni families without TP53 mutations.

Radiation-induced G1 arrest was studied in four classes of early passage skin fibroblasts comprising 12 normals, 12 heterozygous (mut/wt) TP53 mutation-carriers, two homozygous (mut/-) TP53 mutation-carriers and 16 strains from nine Li-Fraumeni syndrome or Li-Fraumeni-like families in which no TP53 mutation has been found, despite sequencing of all exons, exon-intron boundaries, 3' and 5' untranslated regions and promoter regions. In an assay of p53 allelic expression in yeast, cDNAs from these non-mutation strains behaved as wild-type p53. Using two different assays, we found G1 arrest was reduced in heterozygous strains with mis-sense mutations and one truncation mutation, when compared to the range established for the normal cells. Heterozygous strains with mutations at splice sites behaved like normal cells, whilst homozygous (mut/-) strains showed either extremely reduced, or no, arrest. Strains from all nine non-mutation families gave responses within the normal range. Exceptions to the previously reported inverse correlation between G1 arrest and clonogenic radiation resistance were observed, indicating that these phenotypes are not strictly interdependent.  (+info)

(2/153) Exclusion of the genes CDKN2 and PTEN as causative gene defects in Li-Fraumeni syndrome.

We have analysed Li-Fraumeni syndrome families, previously shown to be negative for mutations in TP53, for mutations to the tumour suppressor genes PTEN and CDKN2. These genes function in cell cycle progression or are mutated in a variety of tumours. We have detected no mutations in the family members tested.  (+info)

(3/153) p53 compound heterozygosity in a severely affected child with Li-Fraumeni syndrome.

The Li-Fraumeni Syndrome (LFS) is a rare, dominantly inherited syndrome that features high risk of cancers in childhood and early adulthood. Affected families tend to develop bone and soft tissue sarcomas, breast cancers, brain tumors, leukemias, and adrenocortical carcinomas. In some kindreds, the genetic abnormality associated with this cancer phenotype is a heterozygous germline mutation in the p53 tumor suppressor gene. Recently, we identified one patient who presented in early childhood with multiple primary cancers and who harbored three germline p53 alterations (R156H and R267Q on the maternal allele and R290H on the paternal allele). To classify the biologic effects of these alterations, functional properties of each of the p53 mutants were examined using in vitro assays of cellular growth suppression and transcriptional activation. Each amino acid substitution conferred partial or complete loss of wild-type p53 function, but the child completed normal embryonic development. This observation has not been previously reported in a human, but is consistent with observations of normal embryogenesis in p53-deficient mice.  (+info)

(4/153) Are there low-penetrance TP53 Alleles? evidence from childhood adrenocortical tumors.

We have analyzed a panel of 14 cases of childhood adrenocortical tumors unselected for family history and have identified germline TP53 mutations in >80%, making this the highest known incidence of a germline mutation in a tumor-suppressor gene in any cancer. The spectrum of germline TP53 mutations detected is remarkably limited. Analysis of tumor tissue for loss of constitutional heterozygosity, with respect to the germline mutant allele and the occurrence of other somatic TP53 mutations, indicates complex sequences of genetic events in a number of tumors. None of the families had cancer histories that conformed to the criteria for Li-Fraumeni syndrome, but, in some families, we were able to demonstrate that the mutation had been inherited. In these families there were gene carriers unaffected in their 40s and 50s, and there were others with relatively late-onset cancers. These data provide evidence that certain TP53 alleles confer relatively low penetrance for predisposition to the development of cancer, and they imply that deleterious TP53 mutations may be more frequent in the population than has been estimated previously. Our findings have considerable implications for the clinical management of children with andrenocortical tumors and their parents, in terms of both genetic testing and the early detection and treatment of tumors.  (+info)

(5/153) Human cells compromised for p53 function exhibit defective global and transcription-coupled nucleotide excision repair, whereas cells compromised for pRb function are defective only in global repair.

After exposure to DNA-damaging agents, the p53 tumor suppressor protects against neoplastic transformation by inducing growth arrest and apoptosis. A series of investigations has also demonstrated that, in UV-exposed cells, p53 regulates the removal of DNA photoproducts from the genome overall (global nucleotide excision repair), but does not participate in an overlapping pathway that removes damage specifically from the transcribed strand of active genes (transcription-coupled nucleotide excision repair). Here, the highly sensitive ligation-mediated PCR was employed to quantify, at nucleotide resolution, the repair of UVB-induced cyclobutane pyrimidine dimers (CPDs) in genetically p53-deficient Li-Fraumeni skin fibroblasts, as well as in human lung fibroblasts expressing the human papillomavirus (HPV) E6 oncoprotein that functionally inactivates p53. Lung fibroblasts expressing the HPV E7 gene product, which similarly inactivates the retinoblastoma tumor-suppressor protein (pRb), were also investigated. pRb acts downstream of p53 to mediate G(1) arrest, but has no demonstrated role in DNA repair. Relative to normal cells, HPV E6-expressing lung fibroblasts and Li-Fraumeni skin fibroblasts each manifested defective CPD repair along both the transcribed and nontranscribed strands of the p53 and/or c-jun loci. HPV E7-expressing lung fibroblasts also exhibited reduced CPD removal, but only along the nontranscribed strand. Our results provide striking evidence that transcription-coupled repair, in addition to global repair, are p53-dependent in UV-exposed human fibroblasts. Moreover, the observed DNA-repair defect in HPV E7-expressing cells reveals a function for this oncoprotein in HPV-mediated carcinogenesis, and may suggest a role for pRb in global nucleotide excision repair.  (+info)

(6/153) Heterozygous germ line hCHK2 mutations in Li-Fraumeni syndrome.

The hCHK2 gene encodes the human homolog of the yeast Cds1 and Rad53 G2 checkpoint kinases, whose activation in response to DNA damage prevents cellular entry into mitosis. Here, it is shown that heterozygous germ line mutations in hCHK2 occur in Li-Fraumeni syndrome, a highly penetrant familial cancer phenotype usually associated with inherited mutations in the TP53 gene. These observations suggest that hCHK2 is a tumor suppressor gene conferring predisposition to sarcoma, breast cancer, and brain tumors, and they also provide a link between the central role of p53 inactivation in human cancer and the well-defined G2 checkpoint in yeast.  (+info)

(7/153) Elevated frequency and functional activity of a specific germ-line p53 intron mutation in familial breast cancer.

Previous studies have determined that the frequency of germ-line p53 mutations in familial breast cancer patients is 1% or less, but these reports have not investigated the importance of polymorphic intron base changes in the p53 gene. Therefore, we investigated the frequency of both exon and intron germ-line p53 base changes in 42 breast cancer patients with a strong family history of breast cancer. The mean age of presentation of these patients was 44.0 years (range, 29-69), and 12 of 42 (29%) were of known Ashkenazi ancestry. Purified DNA obtained from the 42 index cases was screened for germ-line p53 mutations in exons 2-11 and surrounding introns using a combination of intron based primers for PCR-single strand conformation polymorphism analysis, direct sequencing, and microarray sequencing using the Affymetrix p53 gene chip methodology. Morphological analysis of apoptosis and cell survival determination were performed on EBV-immortalized lymphoblastoid cell lines from two patients with the p53 intron 6 mutation. A germ-line mutation in the p53 gene at nucleotide 13964 with a G to C base change (13964GC) was identified in 3 of 42 (7.1%) hereditary breast cancer patients. Two patients were heterozygous for this mutation, and one patient had a homozygous mutation. In comparison, 0 of 171 (0%) of sporadic breast cancer patients had the p53 13964GC mutation (P = 0.0003). We found that 0 of 42 (0%) of these hereditary breast cancer patients had other germ-line p53 mutation in exons 2-11. However, pedigree analysis demonstrated that all three patients had strong family histories of multiple types of cancers consistent with Li-Fraumeni syndrome but with late age of onset. Comprehensive BRCA1 and BRCA2 nucleotide analysis from patients with the p53 13964GC mutation revealed no concomitant deleterious BRCA1 or BRCA2 mutations, although they were found in the other hereditary breast cancer patients. Functional analysis of two immortalized lymphoblastoid cell lines derived from patients with the p53 13964GC mutation demonstrated prolonged in vitro survival in response to cisplatinum treatment and showed decreased chemotherapy-induced apoptosis. Immunohistochemical analysis of breast tumors from these patients revealed high levels of mutant p53 protein, suggesting a functional mutation in the p53 gene. In summary, we have identified a single p53 intron mutation in familial breast cancer patients that is present at elevated frequency and has functional activity.  (+info)

(8/153) Genomic alterations associated with loss of heterozygosity for TP53 in Li-Fraumeni syndrome fibroblasts.

Studies of Li-Fraumeni syndrome fibroblasts heterozygous for germline TP53 mutations have shown that loss of heterozygosity (LOH) occurs during passaging and is associated with genomic instability, such as chromosomal aberrations and aneuploidy to investigate the genomic changes associated with LOH in Li-Fraumeni (LF) fibroblasts, we have analysed cell strains at increasing population doublings (PD) using Comparative Genomic Hybridization (CGH). We have looked at three groups of cell strains: LF mutation-carrying strains which showed LOH for TP53, LF mutation-carrying strains which did not show LOH, and strains from normal individuals. Using CGH, we have detected loss of distinct chromosomal regions associated with LOH in 4 out of 5 mutation-carrying strains. In particular we have found loss of chromosomal regions containing genes involved in cell cycle control or senescence, including loss of 9p and 17p in these strains. Other recurrent changes included loss of chromosomes 4q and 6q, regions shown to contain one or more tumour suppressor genes. No genomic alterations were detected at cumulative PD in the normal strains or in the LF mutation-carrying strains which did not show LOH for TP53. We have also analysed the three groups of strains for microsatellite instability and somatic TP53 mutations, and have found genetic alterations in only one strain.  (+info)