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,…
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{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). For BRCA1 mutation carriers, 5-year survival was 63% vs. 91% for noncarriers (p = 0.04). For CaNO ...
Breast cancer is the most prevalent cancer among women, and approximately 10% of all breast cancers are hereditary. The two best known breast cancer susceptibility genes, BRCA1 and BRCA2, were identified 20 years ago, but mutations in these genes account for ~40% of inherited breast cancers. Since then, other genes including ATM, BARD1, BLM, BRIP1, CHEK2, NBS1, PALB2, PTEN, RINT1, TP53 and XRCC2 have been proposed as candidate breast cancer susceptibility genes and together account for another ~10% of hereditary breast cancer families. However, the genes responsible for the other 50% of hereditary cases are yet to be identified.. Certain populations like the French Canadian population of Quebec are notable for the presence of founder mutations that are the result of their presence in a small number of original settlers. Our team has contributed significantly to the identification, characterization and clinical application of founder mutations in BRCA1, BRCA2 and, most recently, PALB2. ...
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Hereditary breast cancer is mainly attributed toloss‐of‐function mutations in and genes, which constitute the most important of the known breast cancer susceptibility genes in terms of high penetrance and clinical significance
Genetic susceptibility factors are associated with most types of cancer, but few of these genes have been identified. We have generated mutant mouse strains with engineered modifications of genes shown to be strongly linked to cancer. We have also adopted comparison genomic hybridization array screening as well as a Drosophila genetic modifier screening methods to identify novel genes linked to cancer. One of our areas of interest is DNA repair. We studied mutant mice lacking MSH2, a component of the DNA mismatch repair machinery. MSH2-deficient mice spontaneously develop tumours early in life, making them a useful model for the study of tumorigenesis, carcinogens and anti-cancer agents. Studies of mice lacking the breast cancer susceptibility genes Brca1 or Brca2 suggest that these proteins have roles in pathways controlling DNA damage repair and the maintenance of genome stability. One of the most important tumour suppressor genes (TSG) for human cancer is p53, a multi- functional protein that ...
Pathogenic mutations in breast cancer susceptibility genes BRCA1 and BRCA2 increase risks for breast, ovarian, fallopian tube, and peritoneal cancer in women; i...
The Food and Drug Administration on Friday approved AstraZeneca PLCs Lynparza for patients with inherited BRCA gene mutations who have undergone chemotherapy. Lynparza will cost $13,886 per month without insurance, according to AstraZeneca. Susan M. Domchek at the University of Pennsylvanias Abramson Cancer Center said in a statement.
Researchers at Huntsman Cancer Institute at the University of Utah have discovered four new genes that increase breast cancer risk when mutated.. The team, who lead an international consortium with the aim of locating more gene mutations that may cause inherited breast cancer susceptibilities, have added RINT1, MRE11A, RAD50 and NBN to the growing list of higher risk genes.. Before a cell becomes cancerous, a number of mistakes need to be present in its genetic code. These mistakes are referred to as mutations.. It is possible to be born with a gene mutation that may increase the risk of cancer. This mutation does not mean the individual will categorically suffer from a form of cancer, but the individual will be more likely to develop cancer than the average person.. Inherited cases of breast cancer are usually associated with two abnormal genes: BRCA1 and BRCA2.. BRCA1 and BRACA2 genes are present in everyone. Their functions are to repair cell damage and ensure normal growth of breast cells. ...
This gene encodes a nuclear phosphoprotein that plays a role in maintaining genomic stability, and it also acts as a tumor suppressor. The encoded protein combines with other tumor suppressors, DNA damage sensors, and signal transducers to form a large multi-subunit protein complex known as the BRCA1-associated genome surveillance complex (BASC). This gene product associates with RNA polymerase II, and through the C-terminal domain, also interacts with histone deacetylase complexes. This protein thus plays a role in transcription, DNA repair of double-stranded breaks, and recombination. Mutations in this gene are responsible for approximately 40% of inherited breast cancers and more than 80% of inherited breast and ovarian cancers. Alternative splicing plays a role in modulating the subcellular localization and physiological function of this gene. Many alternatively spliced transcript variants, some of which are disease-associated mutations, have been described for this gene, but the full-length ...
SB transposon mutagenesis is an unbiased approach for identifying candidate BC driver genes. We successfully induced mammary tumors in mice using the K5 promoter driving SB alone or together with stabilized N-terminally truncated β-catenin targeted to the basal layer of the mammary gland (28). Because the K5-Cre promoter is activated in both the luminal and basal cell layers of the mammary gland, transposition also occurs in both layers and not solely in the basal cell layer, as initially observed with the transgenic line expressing the truncated β-catenin. Not surprisingly, mammary tumors induced by our SB system represented all BC histological subtypes, consistent with the premise that the cell of origin for BC derives from either the luminal or basal layers of mammary glands (56, 57).. The SB mouse model provides a unique experimental basis for the identification of BC-associated susceptible genes relevant to the tumor subtypes. To understand the molecular subtypes of tumors induced in our ...
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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 single nucleotide substitutions in the BRCA1 3UTR and that endogenous HuR protein associates with BRCA1 transcripts in ...
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 surprisingly limited co-localization of BRCA2 and RAD51 in the T. brucei nucleus, and we show that BRCA2 mutants display aberrant
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 of 2%-88% of the expected normal length. Two mutations altered the RING finger domain. Sequencing of genomic DNA led to the identification of a mutation in the coding region ...
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 (VUS). Using family history, segregation analysis, co-occurrence and tumor pathology, certain variants have been classified as either
ABSTRACT: BACKGROUND: Recent advances in whole-genome association studies (WGASs) for human cancer risk are beginning to provide the part lists of low-penetrance susceptibility genes. However, statistical analysis in these studies is complicated by the vast number of genetic variants examined and the weak effects observed, as a result of which constraints must be incorporated into the study design and analytical approach. In this scenario, biological attributes beyond the adjusted statistics generally receive little attention and, more importantly, the fundamental biological characteristics of low-penetrance susceptibility genes have yet to be determined. METHODS: We applied an integrative approach for identifying candidate low-penetrance breast cancer susceptibility genes, their characteristics and molecular networks through the analysis of diverse sources of biological evidence. RESULTS: First, examination of the distribution of Gene Ontology terms in ordered WGAS results identified ...
The novel zinc finger protein 121 (ZNF121) has been demonstrated to physically and functionally associate with the MYC oncoprotein to regulate cell proliferation and likely breast cancer development. To further understand how ZNF121 functions in cell proliferation and carcinogenesis, we identified and characterized the interaction of ZNF121 with zinc finger and BRCA1-interacting protein with a KRAB domain 1 (ZBRK1), a breast and ovarian cancer susceptibility protein 1 (BRCA1)-interacting protein, using the yeast two-hybrid assay and other approaches. We also found that ZNF121 bound to BRCA1. Functionally, ZFN121 suppressed the expression of ANG1 and HMGA2, two common downstream targets of ZBRK1 and BRCA1. Interestingly, ZNF121 also regulated the expression of BRCA1 and ZBRK1. These findings suggest that ZNF121 is likely a member of the BRCA1/CtIP/ZBRK1 repressor complex that plays a role in breast cancer ...
BRCA1 / RNF53, 50 µg. BRCA1 (breast and ovarian cancer susceptibility protein 1) is a RING finger protein containing a BRCT domain.
BRCA1 / RNF53, 50 µg. BRCA1 (breast and ovarian cancer susceptibility protein 1) is a RING finger protein containing a BRCT domain.
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 ...
The tumor suppressor BRCA1 regulates the DNA damage response (DDR) and other processes that remain incompletely defined. Among these, BRCA1 heterodimerizes with BARD1 to ubiquitylate targets via its N-terminal E3 ligase activity. Here, it is demonstrated that BRCA1 promotes oxidative metabolism by degrading Oct1 (POU2F1), a transcription factor with proglycolytic and tumorigenic effects. BRCA1 E3 ubiquitin ligase mutation skews cells toward a glycolytic metabolic profile while elevating Oct1 protein. CRISPR-mediated Oct1 deletion reverts the glycolytic phenotype. RNA sequencing (RNAseq) confirms deregulation of metabolic genes downstream of Oct1. BRCA1 mediates Oct1 ubiquitylation and degradation, and mutation of two ubiquitylated Oct1 lysines insulates the protein against BRCA1-mediated destabilization. Oct1 deletion in MCF-7 breast cancer cells does not perturb growth in standard culture, but inhibits growth in soft agar and xenograft assays. In primary breast cancer clinical specimens, Oct1 ...
In a study reported in The New England Journal of Medicine, Antonis C. Antoniou, PhD, Reader in Cancer Risk Prediction and Cancer Research UK Senior Cancer Research Fellow at the University of Cambridge, and colleagues identified lifetime risk of breast cancer in families with germline loss-of-function mutations in PALB2.1 Estimated cumulative risk among female mutation carriers was 14% by 50 years of age and 35% by 70 years of age. Compared with risk in the general UK population, risk was increased eight- to ninefold in mutation carriers aged , 40 years, six- to eightfold in those aged 40 to 60 years, and fivefold in those aged , 60 years.. PALB2 (partner and localizer of BRCA2) was first identified as a protein integral to BRCA2 genome caretaker functions and was also found to interact with BRCA1. Monoallelic loss-of-function mutations have been associated with increased risks of breast and pancreatic cancers. These loss-of-function mutations have been identified in persons from many countries ...
Human breast cancer is usually caused by genetic alterations of somatic cells of the breast, but occasionally, susceptibility to the disease is inherited. Mapping the genes responsible for inherited breast cancer may also allow the identification of early lesions that are critical for the development of breast cancer in the general population. Chromosome 17q21 appears to be the locale of a gene for inherited susceptibility to breast cancer in families with early-onset disease. Genetic analysis yields a lod score (logarithm of the likelihood ratio for linkage) of 5.98 for linkage of breast cancer susceptibility to D17S74 in early-onset families and negative lod scores in families with late-onset disease. Likelihood ratios in favor of linkage heterogeneity among families ranged between 2000:1 and greater than 10(6):1 on the basis of multipoint analysis of four loci in the region. ...
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Publikācijas starptautiski recenzētos zinātniskos izdevumos:. 1.I.Vanags, A.Petersons, V.Ose, I.Ozolanta, V.Kasyanov, J.Laizans, E.Vjaters, J.Gardovskis, A.Vanags. Biomechanical properties of oesophagus wall under loading. Journal of Biomechanics, 2003; 36: 1387 - 1390.. 2.A.Gardovskis, A.Irmejs, E.Miklasevics, V.Borosenko, M.Bitina, I.Melbarde-Gorkusa, A.Vanags, G.Kurzawski, J.Suchy, B.Gorski, J.Gardovskis. Clinical, molecular and geographical features of hereditary breast / ovarian cancer in Latvia. Hereditary Cancer in Clinical Practice, 2005; 3(2): 71 - 76.. 3.A.Irmejs, E.Miklasevics, V.Boroschenko, A.Gardovskis, A.Vanags, I.Melbarde-Gorkusa, M.Bitina, J.Suchy, J.Gardovskis. Pilot study on low penetrance breast and colorectal cancer predisposition markers in Latvia. Hereditary Cancer in Clinical Practice, 2006; 4(1): 48 - 51.. 4.A.Gardovskis, A.Irmejs, E.Miklasevics, V.Borosenko, M.Bitina, I.Melbarde-Gorkusa, A.Vanags, J.Gardovskis. Update on hereditary breast - ovarian cancer in Latvia. ...
In mammalian cells the accumulation of repair proteins to double-strand breaks is a phosphorylation- and ubiquitylation-regulated process. Some of the genes that encode the kinases and ubiquitin ligases in this pathway are cancer predisposition genes, most prominently the breast cancer predisposition gene BRCA1, which encodes a ubiquitin ligase. How BRCA1 ligase activity was regulated following DNA damage was poorly understood. In this review I summarize new data that show a third post-translational modification, by the small ubiquitin like modifier SUMO, is part of the same cascade, enabling and activating DNA damage-regulated processes, including the BRCA1 ligase activity. Cancer Res; 70(10); OF1-3. ©2010 AACR. ...
Most people who develop breast cancer have no family history of the disease, but sometimes thats not always the case. A persons family history, genetics,
SummaryGADD45 is a DNA damage responsive gene, induced following BRCA1 expression. Mutations at GADD45 might substitute for p53 alterations in hereditary breast tumours characterized by wild-type p53. We analyzed GADD45 alterations in 59 (15 BRCA-associated) familial breast carcinomas. No mutations
Antoniou AC, Pharoah PDP, Narod S, Risch HA, Eyfjord JE, Hopper JL, Olsson H, Johannsson O, Borg Å, Pasini B, Radice P, Manoukian S, Eccles DM, Tang N, Olah E, Anton-Culver H, Warner E, Lubinski J, Gronwald J, Gorski B, Tulininus H, Thorlacius S, Eerola H, Nevanlinna H, Syrjäkoski K, Kallioniemi OP, Thompson D, Evans C, Peto J, Lalloo F, Evans DG, Easton DF. Breast and ovarian cancer risks to carriers of the BRCA1 5382insC and 185delAG and BRCA2 6174delT mutations: a combined analysis of 22 population based studies. J Med Genet. 2005; 2004: . Available at: http://jmg.bmj.com/content/42/7/602.short Accessed on: 2014-09-18 ...
Researchers have identified one of the genes linked to hereditary breast cancer, in a Canadian-led study that could open the door to future gene therapies for women susceptible to the disease.
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: BRCA1 and BRCA2 mutations can be inherited from a persons mother or father. Anyone who has inherited a BRCA1 or BRCA2 mutation could be an increase risk of developing breast and ovarian cancer.. Breast cancer statistics - Breast Cancer Society of Canada has ...
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) = 0.14) were independently associated with the risk of breast cancer for BRCA1 mutation carriers [hazard ratio (HR) = 1.17, 95%
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 ≤ 14 years of age, compared to those who experienced menarche at , 14 years of age (37.38±7.60 and 43.30±10.11, respectively, p, 0.001). Additionally, the number of full-term pregnancies was significantly associated with ...
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 BRCA mutations than in sporadic carcinomas (31, 32, 33) In view of the critical role of p53 in cell cycle regulation, it has been postulated that BRCA1 mutant cells with wild-type p53 are less susceptible to ...
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 counseling 59% from BRCA1 and 46% from BRCA2 said they would consider prophylactic mastectomy if their result was positive; 76% of BRCA1 and 50% of BRCA2
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 were pure serous carcinomas or contained ...
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 BRCT(BRCA1)-phosphoprotein interaction and mimics the M177R/K BRCA1 mutation. Reciprocal immunoprecipitation and immunoblotting of BRCA1 and Abraxas was used to ...
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 genes dont function normally and breast cancer risk increases. Abnormal BRCA1 and BRCA2 genes may account for up to 10% of all breast cancers, or 1 out of every 10 cases.. Having an abnormal BRCA1 or BRCA2 gene doesnt mean you will be diagnosed with breast cancer. ...
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 AURKA, was also found to be associated with breast cancer risk in BRCA2 mutation carriers: rs2426618 per-allele HR = 1.10, 95% CI 1.03-1.16, p = ...
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 predictive strength of major determinants. Estrogen receptor (ER) and phosphatase and tensin homologue (PTEN) status were assessed and
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 ESCs using BACs.71 72 These studies, in the laboratory of Shyam Sharan, focused on VUS in the N-terminal PALB2-binding domain and the C-terminal DBD, where ...
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 BRCA2 gene changes have been linked to male breast cancer and possibly prostate, may also be higher. The gene changes can be inherited from either your mothers or fathers side of the family.. Certain people have a higher chance of inheriting ...
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 for the BRCA2 group compared with 8.0 years for the BRCA1 group, and the risk of mortality was found to be 70% greater in ...
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: ...
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 cohort of 439 women with ovarian cancer, which is similar in frequency to the number of carriers of each of the other three ...
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 BRCA2 mutation carrier and telomere length. It is the first study investigating TL in a cohort of genetically ...
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 high-risk clinic population and to evaluate the performance of the BRCAPRO statistical model in predicting the likelihood of a mutation. Design, Setting, and Participants: ...