JAMA：BRCA1/2遗传突变或引发乳腺癌和卵巢癌风险各异

  近日，来自宾夕法尼亚大学等处的研究人员在对超过3.1万名携带BRCA1和BRCA2促癌突变的女性进行分析研究后，发现这两种突变在引发乳腺癌和卵巢癌上存在明显不同的风险；研究结果显示，某些突变或许会使得乳腺癌发病风险明显升高，而其它突变则会使得卵巢癌风险升高，这或许可以帮助进行有效的癌症风险评估、关爱及开发新型的癌症预防措施，相关研究刊登于国际杂志JAMA上。
  研究者Timothy R. Rebbeck博士指出，我们进行了很多努力来阐明如何减少BRCA1和BRCA2遗传性突变相关的癌症风险，但是截至目前为止，揭示携带特殊遗传突变的女性的癌症风险不同的机制上我们仍人知之甚少；本文研究或可帮助我们理解如何如何对携带特殊突变的女性进行个体化的癌症风险评估，这或可指导个体进行癌症的预防和决策。
  文章中，研究者评估了19581名携带BRCA1和11900名携带BRCA2的个体的癌症风险，随后研究者分析了是否BRCA1和BRCA2突变和乳腺癌及卵巢癌发病风险直接相关；研究者鉴别出了BRCA1和BRCA2的公共区域，当该区域突变后就会引发高风险的卵巢癌，而其它区域则和高风险的乳腺癌直接相关。此前研究发现携带BRCA1突变的女性患乳腺癌的风险为59%，患卵巢癌的风险为34%；然而本文研究则表明，经常在德系犹太人中出现的携带BRCA特殊亚型突变可增加女性69%的患乳腺癌的风险，同时会降低个体患卵巢癌的风险。
  研究者表示，理解突变特异性地风险或可为我们提供重要了信息来对BRCA1/2突变携带者进行癌症风险评估，后期还需要进行更多的研究来决定和不同遗传突变相关的绝对风险，以及这些风险差异如何影响临床医生的癌症治疗决策，比如预防性手术等。（转化医学网360zhyx.com）
  以上为转化医学网原创翻译整理，谢绝转载。如需转载，请联系 info@360zhyx.com
转化医学网推荐的原文摘要：

Association of Type and Location of BRCA1 and BRCA2 Mutations With Risk of Breast and Ovarian Cancer
JAMA    doi:10.1001/jama.2014.5985
Timothy R. Rebbeck, PhD1,2; Nandita Mitra, PhD2; Fei Wan, MS2; Olga M. Sinilnikova, PhD†3; Sue Healey4; Lesley McGuffog5; Sylvie Mazoyer, PhD3; Georgia Chenevix-Trench, PhD4; Douglas F. Easton, PhD5; Antonis C. Antoniou, PhD5; Katherine L. Nathanson, MD1,6 ; and the CIMBA Consortium
Importance  Limited information about the relationship between specific mutations in BRCA1 or BRCA2 (BRCA1/2) and cancer risk exists.
Objective  To identify mutation-specific cancer risks for carriers of BRCA1/2.
Design, Setting, and Participants  Observational study of women who were ascertained between 1937 and 2011 (median, 1999) and found to carry disease-associated BRCA1 or BRCA2 mutations. The international sample comprised 19 581 carriers of BRCA1 mutations and 11 900 carriers of BRCA2 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.
Exposures  Mutations of BRCA1 or BRCA2.
Main Outcomes and Measures  Breast and ovarian cancer risks.
Results  Among BRCA1 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 BRCA2 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 BRCA1, 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; P = 2 × 10−6), c.4328 to c.4945 (BCCR2; RHR = 1.34; 95% CI, 1.01-1.78; P = .04), and c. 5261 to c.5563 (BCCR2′, RHR = 1.38; 95% CI, 1.22-1.55; P = 6 × 10−9). 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; P = 9 × 10−17). In BRCA2, we observed multiple BCCRs spanning c.1 to c.596 (BCCR1; RHR = 1.71; 95% CI, 1.06-2.78; P = .03), c.772 to c.1806 (BCCR1′; RHR = 1.63; 95% CI, 1.10-2.40; P = .01), and c.7394 to c.8904 (BCCR2; RHR = 2.31; 95% CI, 1.69-3.16; P = .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; P = 6 × 10−17). The second OCCR spanned c.6645 to c.7471 (OCCR2; RHR = 0.57; 95% CI, 0.41-0.80; P = .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 BRCA1 and BRCA2 mutation carriers.
Conclusions and Relevance  Breast and ovarian cancer risks varied by type and location of BRCA1/2 mutations. With appropriate validation, these data may have implications for risk assessment and cancer prevention decision making for carriers of BRCA1 and BRCA2 mutations.