Genomes and Genes
Summary: 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)
- Schouten P, van Dyk E, Braaf L, Mulder L, Lips E, de Ronde J, et al. Platform comparisons for identification of breast cancers with a BRCA-like copy number profile. Breast Cancer Res Treat. 2013;139:317-27 pubmed publisher..Our findings suggest that it is possible to map copy number data from any other technology in a similar way. ..
- Sandhu S, Schelman W, Wilding G, Moreno V, Baird R, Miranda S, et al. The poly(ADP-ribose) polymerase inhibitor niraparib (MK4827) in BRCA mutation carriers and patients with sporadic cancer: a phase 1 dose-escalation trial. Lancet Oncol. 2013;14:882-92 pubmed publisher..We investigated the safety, tolerability, maximum tolerated dose, pharmacokinetic and pharmacodynamic profiles, and preliminary antitumour activity of niraparib...
- Genois M, Mukherjee A, Ubeda J, Buisson R, Paquet E, Roy G, et al. Interactions between BRCA2 and RAD51 for promoting homologous recombination in Leishmania infantum. Nucleic Acids Res. 2012;40:6570-84 pubmed publisher..Here we show that the Leishmania infantum BRCA2 protein possesses several critical features important for the regulation of DNA recombination at the genetic and ..
- Magwood A, Mundia M, Baker M. High levels of wild-type BRCA2 suppress homologous recombination. J Mol Biol. 2012;421:38-53 pubmed publisher..Thus, high levels of wild-type BRCA2 perturb Rad51-mediated homologous recombination, and relatively normal recombination responses can be restored by rebalancing recombination factors. ..
- Surade S, Blundell T. Structural biology and drug discovery of difficult targets: the limits of ligandability. Chem Biol. 2012;19:42-50 pubmed publisher..In many enzymes, larger conformational rearrangements are required to form the binding site, and these can make fragment-based approaches particularly difficult. ..
- Couch F, Gaudet M, Antoniou A, Ramus S, Kuchenbaecker K, Soucy P, et al. Common variants at the 19p13.1 and ZNF365 loci are associated with ER subtypes of breast cancer and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers. Cancer Epidemiol Biomarkers Prev. 2012;21:645-57 pubmed publisher..These findings can lead to an improved understanding of tumor development and may prove useful for breast and ovarian cancer risk prediction for BRCA1 and BRCA2 mutation carriers. ..
- Barnes D, Lee A, Easton D, Antoniou A. Evaluation of association methods for analysing modifiers of disease risk in carriers of high-risk mutations. Genet Epidemiol. 2012;36:274-91 pubmed publisher..These methods are illustrated by analyses of genetic modifiers of breast and ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. ..
- Gaj P, Kluska A, Nowakowska D, Bałabas A, Piatkowska M, Dabrowska M, et al. High frequency of BRCA1 founder mutations in Polish women with nonfamilial breast cancer. Fam Cancer. 2012;11:623-8 pubmed publisher..We propose offering inexpensive testing for the presence of BRCA1 founder mutations to all Polish women at the time of initial breast cancer diagnosis, regardless of the patient's family history or age of disease onset. ..
- MacInnis R, Bickerstaffe A, Apicella C, Dite G, Dowty J, Aujard K, et al. Prospective validation of the breast cancer risk prediction model BOADICEA and a batch-mode version BOADICEACentre. Br J Cancer. 2013;109:1296-301 pubmed publisher..70 (95% CI 0.66-0.75) and there was no evidence of systematic under- or over-dispersion (P=0.2). BOADICEA is well calibrated for Australian women, and had good discrimination and accuracy at the individual level. ..
- Narod S, Moody J, Rosen B, Fan I, Risch A, Sun P, et al. Estimating survival rates after ovarian cancer among women tested for BRCA1 and BRCA2 mutations. Clin Genet. 2013;83:232-7 pubmed publisher..1% to 10.0%. The mortality advantage for tested women was due, in part, to a lower than expected mortality rate of tested women in the period following genetic testing. ..
- Dutil J, Colon Colon J, Matta J, Sutphen R, Echenique M. Identification of the prevalent BRCA1 and BRCA2 mutations in the female population of Puerto Rico. Cancer Genet. 2012;205:242-8 pubmed publisher..This data is expected to contribute to providing accurate and efficient tools for the clinical management of hereditary breast cancer in Puerto Rico. ..
- Deb S, Jene N, Fox S. Genotypic and phenotypic analysis of familial male breast cancer shows under representation of the HER2 and basal subtypes in BRCA-associated carcinomas. BMC Cancer. 2012;12:510 pubmed publisher..Comparison with sporadic MBCs shows this to be a high-risk population making further recruitment and investigation of this cohort of value in further understanding these uncommon tumours. ..
- Dann R, DeLoia J, Timms K, Zorn K, Potter J, Flake D, et al. BRCA1/2 mutations and expression: response to platinum chemotherapy in patients with advanced stage epithelial ovarian cancer. Gynecol Oncol. 2012;125:677-82 pubmed publisher..The high overall frequency of BRCA deficiency in EOC underscores the importance of tumor profiling as therapies targeting the DNA repair pathway are being investigated. ..
- Zhang Y, Huang M, Zhu Z. AIB1 polymorphisms with breast cancer susceptibility: a pooled analysis of variation in BRCA1/2 mutation carriers and non-carriers. Mol Biol Rep. 2012;39:6881-6 pubmed publisher..23-0.77). Our results do not support the direct association of AIB1 polyglutamine repeat length and breast cancer. However, we found that BRCA1/2 mutation carriers with both alleles ?29 repeats have a higher risk of breast cancer. ..
- Kotsopoulos J, Lubinski J, Salmena L, Lynch H, Kim Sing C, Foulkes W, et al. Breastfeeding and the risk of breast cancer in BRCA1 and BRCA2 mutation carriers. Breast Cancer Res. 2012;14:R42 pubmed..BRCA mutation carriers should be advised of the benefit of breastfeeding in terms of reducing breast cancer risk. ..
- Cherbal F, Salhi N, Bakour R, Adane S, Boualga K, Maillet P. BRCA1 and BRCA2 unclassified variants and missense polymorphisms in Algerian breast/ovarian cancer families. Dis Markers. 2012;32:343-53 pubmed publisher..Evaluation of breast/ovarian cancer risk induced by the eight new missense UVs and common polymorphisms detected in our present work is on going in a larger study. ..
- Maxwell K, Domchek S. Cancer treatment according to BRCA1 and BRCA2 mutations. Nat Rev Clin Oncol. 2012;9:520-8 pubmed publisher..Although the era of molecular medicine and targeted therapies has led to significant changes in the practice of oncology, new challenges continue to arise. ..
- Yang G, Mercado Uribe I, Multani A, Sen S, Shih I, Wong K, et al. RAS promotes tumorigenesis through genomic instability induced by imbalanced expression of Aurora-A and BRCA2 in midbody during cytokinesis. Int J Cancer. 2013;133:275-85 pubmed publisher..Our results suggest that the imbalance in expression of Aurora-A and BRCA2 regulates RAS-induced genomic instability and tumorigenesis...
- Fischer C, Kuchenbäcker K, Engel C, Zachariae S, Rhiem K, Meindl A, et al. Evaluating the performance of the breast cancer genetic risk models BOADICEA, IBIS, BRCAPRO and Claus for predicting BRCA1/2 mutation carrier probabilities: a study based on 7352 families from the German Hereditary Breast and Ovarian Cancer Consortiu. J Med Genet. 2013;50:360-7 pubmed publisher..eCLAUS should not be used for estimating mutation carrier probabilities in clinical settings. Whenever possible, breast tumour molecular marker information should be taken into account. ..
- Antoniou A, Kuchenbaecker K, Soucy P, Beesley J, Chen X, McGuffog L, et al. Common variants at 12p11, 12q24, 9p21, 9q31.2 and in ZNF365 are associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers. Breast Cancer Res. 2012;14:R33 pubmed..049). The present findings, in combination with previously identified modifiers of risk, will ultimately lead to more accurate risk prediction and an improved understanding of the disease etiology in BRCA1 and BRCA2 mutation carriers. ..
- Lee C, Subramanian S, Beck A, Espinosa I, Senz J, Zhu S, et al. MicroRNA profiling of BRCA1/2 mutation-carrying and non-mutation-carrying high-grade serous carcinomas of ovary. PLoS ONE. 2009;4:e7314 pubmed publisher..High grade serous carcinomas as a group exhibit significant miRNA dysregulation in comparison to tubal epithelium and the levels of miR-34c and miR-422b appear to be prognostically important. ..
- Borg A, Haile R, Malone K, Capanu M, Diep A, Torngren T, et al. Characterization of BRCA1 and BRCA2 deleterious mutations and variants of unknown clinical significance in unilateral and bilateral breast cancer: the WECARE study. Hum Mutat. 2010;31:E1200-40 pubmed publisher..Although some VUS inflict chemical differences at conserved residues, suggesting a deleterious effect, the majority are not associated with an increased risk of CBC. ..
- Van Der Kolk D, de Bock G, Leegte B, Schaapveld M, Mourits M, De Vries J, et al. Penetrance of breast cancer, ovarian cancer and contralateral breast cancer in BRCA1 and BRCA2 families: high cancer incidence at older age. Breast Cancer Res Treat. 2010;124:643-51 pubmed publisher..This may justify intensive breast screening as well as oophorectomy even after age 60. The risk of contralateral breast cancer rises approximately 3% per year, which may affect preventive choices. ..
- Holloman W. Unraveling the mechanism of BRCA2 in homologous recombination. Nat Struct Mol Biol. 2011;18:748-54 pubmed publisher..This review highlights recent studies on BRCA2 and its orthologs that have begun to illuminate the molecular mechanisms by which these proteins control homologous recombination. ..
- Théry J, Krieger S, Gaildrat P, Revillion F, Buisine M, Killian A, et al. Contribution of bioinformatics predictions and functional splicing assays to the interpretation of unclassified variants of the BRCA genes. Eur J Hum Genet. 2011;19:1052-8 pubmed publisher..This work highlights the contribution of splicing minigene assays to the assessment of pathogenicity, not only when patient RNA is not available, but also as a tool to improve the accuracy of bioinformatics predictions. ..
- Walker L, Whiley P, Couch F, Farrugia D, Healey S, Eccles D, et al. Detection of splicing aberrations caused by BRCA1 and BRCA2 sequence variants encoding missense substitutions: implications for prediction of pathogenicity. Hum Mutat. 2010;31:E1484-505 pubmed publisher..b>BRCA2 protein function assays indicated that BRCA2p.Glu2663Val, p.Asp2723Gly and p...
- Nikolova T, Ensminger M, Lobrich M, Kaina B. Homologous recombination protects mammalian cells from replication-associated DNA double-strand breaks arising in response to methyl methanesulfonate. DNA Repair (Amst). 2010;9:1050-63 pubmed publisher..Further, they show that HR is the major pathway of protection of cells against DSB formation, killing and genotoxicity following S(N)2-alkylating agents. ..
- Ramus S, Antoniou A, Kuchenbaecker K, Soucy P, Beesley J, Chen X, et al. Ovarian cancer susceptibility alleles and risk of ovarian cancer in BRCA1 and BRCA2 mutation carriers. Hum Mutat. 2012;33:690-702 pubmed publisher..The identification of multiple loci modifying ovarian cancer risk may be useful for counseling women with BRCA1 and BRCA2 mutations regarding their risk of ovarian cancer. ..
- Sanz D, Acedo A, Infante M, Duran M, Perez Cabornero L, Esteban Cardeñosa E, et al. A high proportion of DNA variants of BRCA1 and BRCA2 is associated with aberrant splicing in breast/ovarian cancer patients. Clin Cancer Res. 2010;16:1957-67 pubmed publisher..The identification of splicing disruptions by functional assays is a valuable tool to discriminate between benign polymorphisms and pathogenic mutations. ..
- Malone K, Begg C, Haile R, Borg A, Concannon P, Tellhed L, et al. Population-based study of the risk of second primary contralateral breast cancer associated with carrying a mutation in BRCA1 or BRCA2. J Clin Oncol. 2010;28:2404-10 pubmed publisher..These findings have important clinical relevance regarding the assessment of BRCA1/BRCA2 status in patients with breast cancer and the counseling and clinical management of patients found to carry a mutation. ..
- Banerjee S, Kaye S, Ashworth A. Making the best of PARP inhibitors in ovarian cancer. Nat Rev Clin Oncol. 2010;7:508-19 pubmed publisher..We suggest that it will be crucial to explore novel therapeutic trial strategies and drug combinations, and incorporate robust biomarkers predictive of response if these drugs are to reach their full potential. ..
- Skoulidis F, Cassidy L, Pisupati V, Jonasson J, Bjarnason H, Eyfjord J, et al. Germline Brca2 heterozygosity promotes Kras(G12D) -driven carcinogenesis in a murine model of familial pancreatic cancer. Cancer Cell. 2010;18:499-509 pubmed publisher..We suggest a revised model for tumor suppression by BRCA2 with implications for the therapeutic strategy targeting BRCA2 mutant cancer cells. ..
- Wevers M, Ausems M, Verhoef S, Bleiker E, Hahn D, Hogervorst F, et al. Behavioral and psychosocial effects of rapid genetic counseling and testing in newly diagnosed breast cancer patients: design of a multicenter randomized clinical trial. BMC Cancer. 2011;11:6 pubmed publisher..This study will also provide data on the psychosocial consequences of RGCT and of risk-reducing behavior. The study is registered at the Netherlands Trial Register (NTR1493) and ClinicalTrials.gov (NCT00783822). ..
- Schlacher K, Christ N, Siaud N, Egashira A, Wu H, Jasin M. Double-strand break repair-independent role for BRCA2 in blocking stalled replication fork degradation by MRE11. Cell. 2011;145:529-42 pubmed publisher..Thus, BRCA2 prevents rather than repairs nucleolytic lesions at stalled replication forks to maintain genomic integrity and hence likely suppresses tumorigenesis through this replication-specific function. ..
- Ochiai K, Yoshikawa Y, Yoshimatsu K, Oonuma T, Tomioka Y, Takeda E, et al. Valine 1532 of human BRC repeat 4 plays an important role in the interaction between BRCA2 and RAD51. FEBS Lett. 2011;585:1771-7 pubmed publisher..However, the cancer-associated V1532F mutant exhibited very weak interaction with RAD51. This study used a comparative analysis of BRC4 between animal species to identify V1532 as an important residue that interacts with RAD51. ..
- Costanzo V. Brca2, Rad51 and Mre11: performing balancing acts on replication forks. DNA Repair (Amst). 2011;10:1060-5 pubmed publisher..These novel functions appear to be essential to ensure smooth progression of DNA replication and to promote maintenance of genome stability. ..
- Jeyasekharan A, Ayoub N, Mahen R, Ries J, Esposito A, Rajendra E, et al. DNA damage regulates the mobility of Brca2 within the nucleoplasm of living cells. Proc Natl Acad Sci U S A. 2010;107:21937-42 pubmed publisher..Our findings identify signal-regulated changes in nucleoplasmic protein diffusion as a means to control biochemical reactions in the cell nucleus. ..
- van der Merwe N, Hamel N, Schneider S, Apffelstaedt J, Wijnen J, Foulkes W. A founder BRCA2 mutation in non-Afrikaner breast cancer patients of the Western Cape of South Africa. Clin Genet. 2012;81:179-84 pubmed publisher..Further studies to determine the carrier rate of this variant in the Xhosa and other SA populations are warranted. ..
- Negura L, Uhrhammer N, Negura A, Artenie V, Carasevici E, Bignon Y. Complete BRCA mutation screening in breast and ovarian cancer predisposition families from a North-Eastern Romanian population. Fam Cancer. 2010;9:519-23 pubmed publisher..4589A>G). Medical follow-up for mutation carriers was implemented. Our study is the first molecular investigation of the role of the BRCA genes in breast and ovarian cancer in Romania. ..
- Meindl A, Ditsch N, Kast K, Rhiem K, Schmutzler R. Hereditary breast and ovarian cancer: new genes, new treatments, new concepts. Dtsch Arztebl Int. 2011;108:323-30 pubmed publisher..Other predisposing genes for breast and ovarian cancer have been identified. Clinicians should develop and implement evidence-based treatments on the basis of these new findings. ..
- Brandão R, van Roozendaal K, Tserpelis D, Gomez Garcia E, Blok M. Characterisation of unclassified variants in the BRCA1/2 genes with a putative effect on splicing. Breast Cancer Res Treat. 2011;129:971-82 pubmed publisher..In conclusion, the RNA analysis results clarified the clinical relevance of 6 of the 14 studied UVs and thereby greatly improve the genetic counselling of high-risk breast/ovarian cancer patients carrying these classified variants. ..
- Wang G, Beattie M, Ponce N, Phillips K. Eligibility criteria in private and public coverage policies for BRCA genetic testing and genetic counseling. Genet Med. 2011;13:1045-50 pubmed publisher..Future research and policy discussions can consider how differences in private and public payer policies influence access to genetic technologies and health outcomes. ..
- Beucher A, Birraux J, Tchouandong L, Barton O, Shibata A, Conrad S, et al. ATM and Artemis promote homologous recombination of radiation-induced DNA double-strand breaks in G2. EMBO J. 2009;28:3413-27 pubmed publisher..We suggest that Artemis endonuclease removes lesions or secondary structures, which inhibit end resection and preclude the completion of HR or NHEJ. ..
- Antoniou A, Sinilnikova O, McGuffog L, Healey S, Nevanlinna H, Heikkinen T, et al. Common variants in LSP1, 2q35 and 8q24 and breast cancer risk for BRCA1 and BRCA2 mutation carriers. Hum Mol Genet. 2009;18:4442-56 pubmed publisher..There was no evidence that the associations vary by mutation type depending on whether the mutated protein is predicted to be stable or not. ..
- Adank M, van Mil S, Gille J, Waisfisz Q, Meijers Heijboer H. PALB2 analysis in BRCA2-like families. Breast Cancer Res Treat. 2011;127:357-62 pubmed publisher..We conclude that germline mutations of PALB2 do not significantly contribute to cancer risk in non-BRCA1/2 cancer families with at least one patient with ovarian cancer, male breast cancer, and/or pancreatic cancer. ..