Format:
15
ISSN:
1538-3598
Content:
〈h3〉Importance〈/h3〉〈p〉Limited information about the relationship between specific mutations in〈i〉BRCA1〈/i〉or〈i〉BRCA2〈/i〉(〈i〉BRCA1/2〈/i〉) and cancer risk exists.〈/p〉〈h3〉Objective〈/h3〉〈p〉To identify mutation-specific cancer risks for carriers of〈i〉BRCA1/2〈/i〉.〈/p〉〈h3〉Design, Setting, and Participants〈/h3〉〈p〉Observational study of women who were ascertained between 1937 and 2011 (median, 1999) and found to carry disease-associated〈i〉BRCA1〈/i〉or〈i〉BRCA2〈/i〉mutations. The international sample comprised 19 581 carriers of〈i〉BRCA1〈/i〉mutations and 11 900 carriers of〈i〉BRCA2〈/i〉mutations from 55 centers in 33 countries on 6 continents. We estimated hazard ratios for breast and ovarian cancer based on mutation type, function, and nucleotide position. We also estimated RHR, the ratio of breast vs ovarian cancer hazard ratios. A value of RHR greater than 1 indicated elevated breast cancer risk; a value of RHR less than 1 indicated elevated ovarian cancer risk.〈/p〉〈h3〉Exposures〈/h3〉〈p〉Mutations of〈i〉BRCA1〈/i〉or〈i〉BRCA2.〈/i〉〈/p〉〈h3〉Main Outcomes and Measures〈/h3〉〈p〉Breast and ovarian cancer risks.〈/p〉〈h3〉Results〈/h3〉〈p〉Among〈i〉BRCA1〈/i〉mutation carriers, 9052 women (46%) were diagnosed with breast cancer, 2317 (12%) with ovarian cancer, 1041 (5%) with breast and ovarian cancer, and 7171 (37%) without cancer. Among〈i〉BRCA2〈/i〉mutation carriers, 6180 women (52%) were diagnosed with breast cancer, 682 (6%) with ovarian cancer, 272 (2%) with breast and ovarian cancer, and 4766 (40%) without cancer. In〈i〉BRCA1〈/i〉, we identified 3 breast cancer cluster regions (BCCRs) located at c.179 to c.505 (BCCR1; RHR = 1.46; 95% CI, 1.22-1.74;〈i〉P〈/i〉 = 2 × 10〈sup〉−6〈/sup〉), c.4328 to c.4945 (BCCR2; RHR = 1.34; 95% CI, 1.01-1.78;〈i〉P〈/i〉 = .04), and c. 5261 to c.5563 (BCCR2′, RHR = 1.38; 95% CI, 1.22-1.55;〈i〉P〈/i〉 = 6 × 10〈sup〉−9〈/sup〉). We also identified an ovarian cancer cluster region (OCCR) from c.1380 to c.4062 (approximately exon 11) with RHR = 0.62 (95% CI, 0.56-0.70;〈i〉P〈/i〉 = 9 × 10〈sup〉−17〈/sup〉). In〈i〉BRCA2〈/i〉, we observed multiple BCCRs spanning c.1 to c.596 (BCCR1; RHR = 1.71; 95% CI, 1.06-2.78;〈i〉P〈/i〉 = .03), c.772 to c.1806 (BCCR1′; RHR = 1.63; 95% CI, 1.10-2.40;〈i〉P〈/i〉 = .01), and c.7394 to c.8904 (BCCR2; RHR = 2.31; 95% CI, 1.69-3.16;〈i〉P〈/i〉 = .00002). We also identified 3 OCCRs: the first (OCCR1) spanned c.3249 to c.5681 that was adjacent to c.5946delT (6174delT; RHR = 0.51; 95% CI, 0.44-0.60;〈i〉P〈/i〉 = 6 × 10〈sup〉−17〈/sup〉). The second OCCR spanned c.6645 to c.7471 (OCCR2; RHR = 0.57; 95% CI, 0.41-0.80;〈i〉P〈/i〉 = .001). Mutations conferring nonsense-mediated decay were associated with differential breast or ovarian cancer risks and an earlier age of breast cancer diagnosis for both〈i〉BRCA1〈/i〉and〈i〉BRCA2〈/i〉mutation carriers.〈/p〉〈h3〉Conclusions and Relevance〈/h3〉〈p〉Breast and ovarian cancer risks varied by type and location of〈i〉BRCA1/2〈/i〉mutations. With appropriate validation, these data may have implications for risk assessment and cancer prevention decision making for carriers of〈i〉BRCA1〈/i〉and〈i〉BRCA2〈/i〉mutations.〈/p〉
Note:
Gesehen am 17.06.2020
In:
American Medical Association, The journal of the American Medical Association, Chicago, Ill. : American Medical Association, 1883, 313(2015), 13, Seite 1347-1361, 1538-3598
In:
volume:313
In:
year:2015
In:
number:13
In:
pages:1347-1361
In:
extent:15
Language:
English
DOI:
10.1001/jama.2014.5985
URL:
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