Genomes and Genes
Summary: 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)
- Bradbury A, Ibe C, Dignam J, Cummings S, Verp M, White M, et al. Uptake and timing of bilateral prophylactic salpingo-oophorectomy among BRCA1 and BRCA2 mutation carriers. Genet Med. 2008;10:161-166 pubmed publisher..Some women make this decision many years after genetic testing. Continued discussion of the risks and benefits of risk reduction options may facilitate the uptake of recommended risk reduction interventions among BRCA mutation carriers. ..
- Cvok M, Cretnik M, Musani V, Ozretic P, Levanat S. New sequence variants in BRCA1 and BRCA2 genes detected by high-resolution melting analysis in an elderly healthy female population in Croatia. Clin Chem Lab Med. 2008;46:1376-83 pubmed publisherMutations in BRCA1 and BRCA2 genes are associated with family predisposition to breast and ovarian cancer...
- Hansen T, Bisgaard M, Jønson L, Albrechtsen A, Filtenborg Barnkob B, Eiberg H, et al. Novel de novo BRCA2 mutation in a patient with a family history of breast cancer. BMC Med Genet. 2008;9:58 pubmed publisher..were identified by denaturing high performance liquid chromatography (dHPLC) and sequencing of the BRCA1 and BRCA2 genes. The effect of the mutation on splicing was examined by exon trapping in COS-7 cells and by RT-PCR on RNA ..
- Hansen T, Jønson L, Albrechtsen A, Andersen M, Ejlertsen B, Nielsen F. Large BRCA1 and BRCA2 genomic rearrangements in Danish high risk breast-ovarian cancer families. Breast Cancer Res Treat. 2009;115:315-23 pubmed publisher..Nine patients had the exon 3-16 deletion in BRCA1. By SNP analysis we find that the patients share a 5 Mb fragment of chromosome 17, including BRCA1, indicating that the exon 3-16 deletion represents a Danish founder mutation. ..
- Bennett S, Noor M. Molecular evolution of a Drosophila homolog of human BRCA2. Genetica. 2009;137:213-9 pubmed publisher..Overall, we have documented patterns and modes of evolution in a new model system of a gene which is important to human health...
- Hirst J, Gard G, McIllroy K, Nevell D, Field M. High rates of occult fallopian tube cancer diagnosed at prophylactic bilateral salpingo-oophorectomy. Int J Gynecol Cancer. 2009;19:826-9 pubmed publisher..It supports emerging evidence that the fimbrial end of the fallopian tube is an important site of genesis of cancer in BRCA1/2 mutation carriers. ..
- Evans D, Lalloo F, Ashcroft L, Shenton A, Clancy T, Baildam A, et al. Uptake of risk-reducing surgery in unaffected women at high risk of breast and ovarian cancer is risk, age, and time dependent. Cancer Epidemiol Biomarkers Prev. 2009;18:2318-24 pubmed publisher..Careful risk counseling does seem to influence women's decisions for surgery, although the effect is not immediate. ..
- Evans D, Shenton A, Woodward E, Lalloo F, Howell A, Maher E. Penetrance estimates for BRCA1 and BRCA2 based on genetic testing in a Clinical Cancer Genetics service setting: risks of breast/ovarian cancer quoted should reflect the cancer burden in the family. BMC Cancer. 2008;8:155 pubmed publisher..This is particularly true for women born after 1940. ..
- Thomassen M, Hansen T, Borg A, Lianee H, Wikman F, Pedersen I, et al. BRCA1 and BRCA2 mutations in Danish families with hereditary breast and/or ovarian cancer. Acta Oncol. 2008;47:772-7 pubmed publisher..Based on these observations we recommend that the mutation screening strategy of the BRCA1 and BRCA2 genes in Danish HBOC families comprises full screening of both genes including analysis for large genomic ..
- Köbel M, Huntsman D, Gilks C. Critical molecular abnormalities in high-grade serous carcinoma of the ovary. Expert Rev Mol Med. 2008;10:e22 pubmed publisher..These highly aggressive but chemosensitive tumours are associated with perturbation of molecular pathways leading to genomic instability and extreme mutability and present unique challenges in oncological research and practice...
- Distelman Menachem T, Shapira T, Laitman Y, Kaufman B, Barak F, Tavtigian S, et al. Analysis of BRCA1/BRCA2 genes' contribution to breast cancer susceptibility in high risk Jewish Ashkenazi women. Fam Cancer. 2009;8:127-33 pubmed publisher..None of these abnormalities could be confirmed using quantitative PCR (qPCR) analysis. Major gene rearrangements involving BRCA1 BRCA2 contribute little to the burden of inherited predisposition of breast cancer in Ashkenazi Jews. ..
- Douglas H, Hamilton R, Grubs R. The effect of BRCA gene testing on family relationships: A thematic analysis of qualitative interviews. J Genet Couns. 2009;18:418-35 pubmed publisher..Genetic counselors might find it useful to explore these issues in order to prepare clients before BRCA testing and to support them through shifts in family dynamics after disclosure of results. ..
- Evans D, Lalloo F, Cramer A, Jones E, Knox F, Amir E, et al. Addition of pathology and biomarker information significantly improves the performance of the Manchester scoring system for BRCA1 and BRCA2 testing. J Med Genet. 2009;46:811-7 pubmed publisher..Furthermore, 65 and 58 fewer cases met the 10% and 20% threshold, respectively, for testing. Moreover, the adjusted score significantly improved the trade-off between sensitivity and specificity for BRCA1/2 prediction. ..
- Fong P, Boss D, Yap T, Tutt A, Wu P, Mergui Roelvink M, et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med. 2009;361:123-34 pubmed publisher..Olaparib has few of the adverse effects of conventional chemotherapy, inhibits PARP, and has antitumor activity in cancer associated with the BRCA1 or BRCA2 mutation. (ClinicalTrials.gov number, NCT00516373.) ..
- Matloff E, Barnett R, Bober S. Unraveling the next chapter: sexual development, body image, and sexual functioning in female BRCA carriers. Cancer J. 2009;15:15-8 pubmed publisher..This article will focus on those issues in unaffected female BRCA carriers. ..
- Hansen T, Steffensen A, Jønson L, Andersen M, Ejlertsen B, Nielsen F. The silent mutation nucleotide 744 G --> A, Lys172Lys, in exon 6 of BRCA2 results in exon skipping. Breast Cancer Res Treat. 2010;119:547-50 pubmed publisher..We therefore conclude that the BRCA2 silent mutation Lys172Lys is a disease-causing mutation...
- Antoniou A, Cunningham A, Peto J, Evans D, Lalloo F, Narod S, et al. The BOADICEA model of genetic susceptibility to breast and ovarian cancers: updates and extensions. Br J Cancer. 2008;98:1457-66 pubmed publisher..BOADICEA can be used to predict carrier probabilities and cancer risks to individuals with any family history, and has been implemented in a user-friendly Web-based program (http://www.srl.cam.ac.uk/genepi/boadicea/boadicea_home.html). ..
- Byrd L, Shenton A, Maher E, Woodward E, Belk R, Lim C, et al. Better life expectancy in women with BRCA2 compared with BRCA1 mutations is attributable to lower frequency and later onset of ovarian cancer. Cancer Epidemiol Biomarkers Prev. 2008;17:1535-42 pubmed publisher..Interventions to reduce ovarian cancer incidence are likely to have a greater effect on life expectancy in BRCA1 compared with BRCA2 carriers. ..
- Willems A, Dawson S, Samaratunga H, De Luca A, Antill Y, Hopper J, et al. Loss of heterozygosity at the BRCA2 locus detected by multiplex ligation-dependent probe amplification is common in prostate cancers from men with a germline BRCA2 mutation. Clin Cancer Res. 2008;14:2953-61 pubmed publisher..We examined LOH at the BRCA1 and BRCA2 genes using multiplex ligation-dependent probe amplification of DNA from microdissected tumor...
- Howard A, Balneaves L, Bottorff J. Women's decision making about risk-reducing strategies in the context of hereditary breast and ovarian cancer: a systematic review. J Genet Couns. 2009;18:578-97 pubmed publisherWomen who have a mutation in the BRCA1 or BRCA2 genes have up to an 87% lifetime risk of breast cancer and up to a 40% lifetime risk of ovarian cancer...
- Vidal Millan S, Taja Chayeb L, Gutiérrez Hernández O, Ramírez Ugalde M, Robles Vidal C, Bargallo Rocha E, et al. Mutational analysis of BRCA1 and BRCA2 genes in Mexican breast cancer patients. Eur J Gynaecol Oncol. 2009;30:527-30 pubmedGermline mutations in the BRCA1 and BRCA2 genes predispose to breast and ovarian cancer. A variable incidence of mutations has been reported for these genes...
- Ashworth A. Drug resistance caused by reversion mutation. Cancer Res. 2008;68:10021-3 pubmed publisherCells carrying mutated BRCA1 or BRCA2 genes are defective in DNA repair by homologous recombination and, as a consequence, are highly sensitive to inhibitors of poly (ADP-ribose) polymerase (PARP)...
- Narod S, Neuhausen S, Vichodez G, Armel S, Lynch H, Ghadirian P, et al. Rapid progression of prostate cancer in men with a BRCA2 mutation. Br J Cancer. 2008;99:371-4 pubmed publisher..0 years for men with a BRCA1 mutation, and the difference was highly significant (P<0.01). It may be important to develop targeted chemotherapies to treat prostate cancer in men with a BRCA2 mutation. ..
- Folkins A, Jarboe E, Roh M, Crum C. Precursors to pelvic serous carcinoma and their clinical implications. Gynecol Oncol. 2009;113:391-6 pubmed publisher..The data supporting a candidate precursor, the implications of these findings for early detection and prevention of pelvic serous carcinoma and the caveats, are discussed...
- Milne R, Osorio A, Cajal T, Vega A, Llort G, de la Hoya M, et al. The average cumulative risks of breast and ovarian cancer for carriers of mutations in BRCA1 and BRCA2 attending genetic counseling units in Spain. Clin Cancer Res. 2008;14:2861-9 pubmed publisher..Carriers should be fully informed of their mutation- and age-specific risks to make appropriate decisions regarding prophylactic interventions such as oophorectomy. ..
- Martin S, Lord C, Ashworth A. DNA repair deficiency as a therapeutic target in cancer. Curr Opin Genet Dev. 2008;18:80-6 pubmed publisher..It seems likely that other DNA repair processes can be targeted in a similar manner. These synthetic lethal approaches highlight how an understanding of DNA repair processes can be used in the development of novel cancer treatments. ..
- Metcalfe K, Lubinski J, Ghadirian P, Lynch H, Kim Sing C, Friedman E, et al. Predictors of contralateral prophylactic mastectomy in women with a BRCA1 or BRCA2 mutation: the Hereditary Breast Cancer Clinical Study Group. J Clin Oncol. 2008;26:1093-7 pubmed publisher..The acceptance of contralateral preventive mastectomy was much higher in North America than in Europe. ..
- Syamala V, Sreeja L, Syamala V, Vinodkumar B, Raveendran P, Sreedharan H, et al. Novel germline mutations in BRCA2 gene among 96 hereditary breast and breast-ovarian cancer families from Kerala, South India. J Cancer Res Clin Oncol. 2007;133:867-74 pubmed..The results of this study suggest that germline mutations of BRCA2 gene account for rather small proportion of Hereditary Breast/Ovarian cancer in Kerala, South India. ..
- Friebel T, Domchek S, Neuhausen S, Wagner T, Evans D, Isaacs C, et al. Bilateral prophylactic oophorectomy and bilateral prophylactic mastectomy in a prospective cohort of unaffected BRCA1 and BRCA2 mutation carriers. Clin Breast Cancer. 2007;7:875-82 pubmed publisher..Parity, age, and family history can also influence BPO and BPM uptake. Consistent with current recommendations, BPO is used by the majority of parous women aged > 40 years. ..
- Smirnova T, Pospekhova N, Lyubchenko L, Tjulandin S, Gar kavtseva R, Ginter E, et al. High incidence of mutations in BRCA1 and BRCA2 genes in ovarian cancer. Bull Exp Biol Med. 2007;144:83-5 pubmedThe incidence of mutations in the BRCA1 and BRCA2 genes in the studied sampling of 74 patients with ovarian cancer was 19%...
- Tai Y, Domchek S, Parmigiani G, Chen S. Breast cancer risk among male BRCA1 and BRCA2 mutation carriers. J Natl Cancer Inst. 2007;99:1811-4 pubmed..The estimated cumulative risk of breast carcinoma for male BRCA1 mutation carriers at age 70 years was 1.2% (95% confidence interval [CI] = 0.22% to 2.8%) and for BRCA2 mutation carriers, 6.8% (95% CI = 3.2% to 12%). ..
- Robson M, Offit K. Clinical practice. Management of an inherited predisposition to breast cancer. N Engl J Med. 2007;357:154-62 pubmed
- Couch F, Sinilnikova O, Vierkant R, Pankratz V, Fredericksen Z, Stoppa Lyonnet D, et al. AURKA F31I polymorphism and breast cancer risk in BRCA1 and BRCA2 mutation carriers: a consortium of investigators of modifiers of BRCA1/2 study. Cancer Epidemiol Biomarkers Prev. 2007;16:1416-21 pubmed..In summary, the F31I polymorphism in AURKA is not associated with a modified risk of breast cancer in BRCA1 and BRCA2 carriers. ..
- Brohet R, Goldgar D, Easton D, Antoniou A, Andrieu N, Chang Claude J, et al. Oral contraceptives and breast cancer risk in the international BRCA1/2 carrier cohort study: a report from EMBRACE, GENEPSO, GEO-HEBON, and the IBCCS Collaborating Group. J Clin Oncol. 2007;25:3831-6 pubmed..However, duration of use, especially before first full-term pregnancy, may be associated with an increasing risk of breast cancer among both BRCA1 and BRCA2 mutation carriers. ..
- King T, Li W, Brogi E, Yee C, Gemignani M, Olvera N, et al. Heterogenic loss of the wild-type BRCA allele in human breast tumorigenesis. Ann Surg Oncol. 2007;14:2510-8 pubmed
- Dent R, Warner E. Screening for hereditary breast cancer. Semin Oncol. 2007;34:392-400 pubmed..This review will examine the literature and current screening recommendations. ..
- Tryggvadottir L, Vidarsdottir L, Thorgeirsson T, Jonasson J, Olafsdóttir E, Olafsdóttir G, et al. Prostate cancer progression and survival in BRCA2 mutation carriers. J Natl Cancer Inst. 2007;99:929-35 pubmed..The Icelandic BRCA2 999del5 founder mutation was strongly associated with rapidly progressing lethal prostate cancer. ..
- Begg C, Haile R, Borg A, Malone K, Concannon P, Thomas D, et al. Variation of breast cancer risk among BRCA1/2 carriers. JAMA. 2008;299:194-201 pubmed publisher..28). In addition, there were significant differences in risk between carrier families after adjusting for these observed characteristics. There exists broad variation in breast cancer risk among carriers of BRCA1 and BRCA2 mutations. ..
- Mitra A, Fisher C, Foster C, Jameson C, Barbachanno Y, Bartlett J, et al. Prostate cancer in male BRCA1 and BRCA2 mutation carriers has a more aggressive phenotype. Br J Cancer. 2008;98:502-7 pubmed publisher..Targeting screening to this population may detect disease at an earlier clinical stage which may therefore be beneficial. ..
- Edwards S, Brough R, Lord C, Natrajan R, Vatcheva R, Levine D, et al. Resistance to therapy caused by intragenic deletion in BRCA2. Nature. 2008;451:1111-5 pubmed publisher..6174delT mutation carriers. These observations have implications for understanding drug resistance in BRCA mutation carriers as well as in defining functionally important domains within BRCA2. ..
- Li H, Giger M, Olopade O, Lan L. Fractal analysis of mammographic parenchymal patterns in breast cancer risk assessment. Acad Radiol. 2007;14:513-21 pubmed..We believe that the proposed analyses based on the LDA technique to characterize mammographic parenchymal patterns may potentially yield radiographic markers for assessing breast cancer risk. ..
- Wacholder S, Loukissas J, Hartge P. Studies of genes and cancer survival: pieces of the puzzle. J Natl Cancer Inst. 2007;99:908-9 pubmed
- Chang Claude J, Andrieu N, Rookus M, Brohet R, Antoniou A, Peock S, et al. Age at menarche and menopause and breast cancer risk in the International BRCA1/2 Carrier Cohort Study. Cancer Epidemiol Biomarkers Prev. 2007;16:740-6 pubmed..The absence of an effect of age at natural menopause is, however, not consistent with findings in the general population and may reflect the different natural history of the disease in carriers. ..
- Mitra A, Bancroft E, Eeles R. A review of targeted screening for prostate cancer: introducing the IMPACT study. BJU Int. 2007;99:1350-5 pubmed
- Agalliu I, Karlins E, Kwon E, Iwasaki L, Diamond A, Ostrander E, et al. Rare germline mutations in the BRCA2 gene are associated with early-onset prostate cancer. Br J Cancer. 2007;97:826-31 pubmed..However, we estimate that <1% of early-onset prostate cancers in the general US Caucasian population can be attributed to these rare disease-associated BRCA2 mutations. ..
- Ang P, Lim I, Lee T, Luo J, Ong D, Tan P, et al. BRCA1 and BRCA2 mutations in an Asian clinic-based population detected using a comprehensive strategy. Cancer Epidemiol Biomarkers Prev. 2007;16:2276-84 pubmedGenetic testing for germ line mutations in the BRCA1 and BRCA2 genes for some families at high risk for breast and/or ovarian cancer may yield negative results due to unidentified mutations or mutations with unknown clinical significance...
- Klovstad M, Abdu U, Schupbach T. Drosophila brca2 is required for mitotic and meiotic DNA repair and efficient activation of the meiotic recombination checkpoint. PLoS Genet. 2008;4:e31 pubmed publisher..In addition, Brca2 co-immunoprecipitates with the checkpoint protein Rad9, suggesting a direct role for Brca2 in the transduction of the meiotic recombination checkpoint signal. ..
- Smith A, Dougall A, POSLUSZNY D, Somers T, Rubinstein W, Baum A. Psychological distress and quality of life associated with genetic testing for breast cancer risk. Psychooncology. 2008;17:767-73 pubmed..However, sub-groups of women may report more distress over time. These data indicate the need for more targeted counseling to individuals who report high levels of distress when considering genetic testing. ..
- Melchor L, Honrado E, Huang J, Alvarez S, Naylor T, Garcia M, et al. Estrogen receptor status could modulate the genomic pattern in familial and sporadic breast cancer. Clin Cancer Res. 2007;13:7305-13 pubmed..According to our results, the BRCA gene mutation status (mainly BRCA1) would contribute to the genomic profile of abnormalities by increasing or modulating the genome instability. ..
- Moller P, Evans D, Reis M, Gregory H, Anderson E, Maehle L, et al. Surveillance for familial breast cancer: Differences in outcome according to BRCA mutation status. Int J Cancer. 2007;121:1017-20 pubmed
- Kauff N, Domchek S, Friebel T, Robson M, Lee J, Garber J, et al. Risk-reducing salpingo-oophorectomy for the prevention of BRCA1- and BRCA2-associated breast and gynecologic cancer: a multicenter, prospective study. J Clin Oncol. 2008;26:1331-7 pubmed publisher..Further studies evaluating the efficacy of risk-reduction strategies in BRCA mutation carriers should stratify by the specific gene mutated. ..