Citations 2
Biallelic Deleterious BRCA1 Mutations in a Woman with Early-Onset Ovarian Cancer
Tang, Jiang-bo, Stopfer, Jill E. , Lilli, Dana R., Hamel, Nancy , Monteiro, Álvaro N.A. , Messick, Troy E. , Powers, Jacquelyn M. , Yonker, Alexandria, Goldgar, David E., Davidson, H. Rosemarie, Nathanson, Katherine L. , Domchek, Susan M. , Tischkowitz, Marc D. , Couch, Fergus J. , Foulkes, William D. , Greenberg, Roger A. , Monteiro, Alvaro N , Nathanson, Katherine L
Cancer Discovery | December 26, 2012 | Volume: 3 | Issue: 4 | Pages: 399-405
Abstract BRCA1 and BRCA2 are the most important breast and ovarian cancer susceptibility genes. Biallelic mutations in BRCA2 can lead to Fanconi anemia and predisposition to cancers, whereas biallelic BRCA1 mutations have not been confirmed, presumably because one wild-type BRCA1 allele is required during embryogenesis. This study describes an individual who was diagnosed with ovarian carcinoma at age 28 and found to have one allele with a deleterious mutation in BRCA1, c.2457delC (p.Asp821Ilefs*25), and a second allele with a variant of unknown significance in BRCA1, c.5207T>C (p.Val1736Ala). Medical records revealed short stature, microcephaly, developmental delay, and significant toxicity from chemotherapy. BRCA1 p.Val1736Ala cosegregated with cancer in multiple families, associated tumors showed loss of wild-type BRCA1, and BRCA1 p.Val1736Ala showed reduced DNA damage localization. These findings represent the first validated example of biallelic deleterious human BRCA1 mutations and have implications for the interpretation of genetic test results. Significance: Accurate assessment of genetic testing data for BRCA1 mutations is essential for clinical monitoring and treatment strategies. Here, we report the first validated example of an individual with biallelic BRCA1 mutations, early-onset ovarian cancer, and clinically significant hypersensitivity to chemotherapy. Cancer Discov; 3(4); 399–405. ©2012 AACR. See related commentary by D'Andrea, p. 376 This article is highlighted in the In This Issue feature, p. 363
Multiple Novel Prostate Cancer Predisposition Loci Confirmed by an International Study: The PRACTICAL Consortium
Easton, Douglas F. , Stanford, Janet L. , Ostrander, Elaine A. , Schleutker, Johanna , Schaid, Daniel J. , Thibodeau, Stephen N. , Dörk, Thilo , Neal, David E. , Cox, Angela , Maier, Christiane, Guy, Michelle, Lophatananon, Artitaya, Kedda, Mary-Anne, Spurdle, Amanda B. , Steginga, Suzanne K., John, Esther M. , Giles, Graham G. , Chappuis, Pierre O. , Hutter, Pierre, Foulkes, William D. , Hamel, Nancy , Salinas, Claudia A., Karyadi, Danielle M. , Johanneson, Bo, Wahlfors, Tiina , Tammela, Teuvo L.J. , Corral, Román, McDonnell, Shannon K. , Schürmann, Peter , Meyer, Andreas , Kuefer, Rainer, Leongamornlert, Daniel , Tymrakiewicz, Malgorzata, Liu, Jo‐Fen , O’Mara, Tracy A. , Gardiner, Robert A. , Aitken, Joanne F. , Joshi, Amit D. , Severi, Gianluca , English, Dallas R. , Southey, Melissa C. , Edwards, Stephen M., Olama, Ali Amin Al , Eeles, Rosalind A. , Donovan, Jenny , Chambers, Suzanne K. , Kote‐Jarai, Zsofia , Ingles, Sue A. , Vogel, W. , Muir, Kenneth , Hopper, John L. , Koopmeiners, Joseph Stephen , Stern, Mariana Carla , Dörk, Thilo , Giles, Graham G , Spurdle, Amanda B , Foulkes, William D , Eeles, Rosalind A , John, Esther M , Southey, Melissa C , English, Dallas R , Donovan, Jenny L , Schleutker, Johanna , O'Mara, Tracy A , Cox, Angela , Severi, Gianluca , McDonnell, Shannon K
Cancer Epidemiology, Biomarkers & Prevention | August 15, 2008 | Volume: 17 | Issue: 8 | Pages: 2052-2061
Abstract A recent genome-wide association study found that genetic variants on chromosomes 3, 6, 7, 10, 11, 19 and X were associated with prostate cancer risk. We evaluated the most significant single-nucleotide polymorphisms (SNP) in these loci using a worldwide consortium of 13 groups (PRACTICAL). Blood DNA from 7,370 prostate cancer cases and 5,742 male controls was analyzed by genotyping assays. Odds ratios (OR) associated with each genotype were estimated using unconditional logistic regression. Six of the seven SNPs showed clear evidence of association with prostate cancer (P = 0.0007-P = 10−17). For each of these six SNPs, the estimated per-allele OR was similar to those previously reported and ranged from 1.12 to 1.29. One SNP on 3p12 (rs2660753) showed a weaker association than previously reported [per-allele OR, 1.08 (95% confidence interval, 1.00-1.16; P = 0.06) versus 1.18 (95% confidence interval, 1.06-1.31)]. The combined risks associated with each pair of SNPs were consistent with a multiplicative risk model. Under this model, and in combination with previously reported SNPs on 8q and 17q, these loci explain 16% of the familial risk of the disease, and men in the top 10% of the risk distribution have a 2.1-fold increased risk relative to general population rates. This study provides strong confirmation of these susceptibility loci in multiple populations and shows that they make an important contribution to prostate cancer risk prediction. (Cancer Epidemiol Biomarkers Prev 2008;17(8):2052–61)