Mai Phuong L, Chatterjee Nilanjan, Hartge Patricia, Tucker Margaret, Brody Lawrence, Struewing Jeffery P, Wacholder Sholom
Clinical Genetic Branch, National Cancer Institute, Rockville, Maryland, United States of America.
PLoS One. 2009;4(3):e4812. doi: 10.1371/journal.pone.0004812. Epub 2009 Mar 11.
Although the increase in risk of developing breast, ovarian, and prostate cancer in BRCA1 and BRCA2 mutation carriers has been studied extensively, its impact on mortality is not well quantified. Further, possible effect of BRCA mutations on non-cancer mortality risk has not been examined.
METHODOLOGY/PRINCIPAL FINDINGS: Using mortality data from the relatives of 5,287 genotyped participants, of whom 120 carried a BRCA Ashkenazi Jewish founder mutation, in a community-based study of the Ashkenazi Jewish population in the Washington D.C area, we examined the association between the three Ashkenazi BRCA founder mutations and risk of overall and non-cancer mortality. To examine risks beyond the established effects of these mutations, we analyzed the data excluding both deaths and follow-up times after reported diagnosis of melanoma and cancer of the breast, ovary, prostate, and pancreas. Using an extension of the kin-cohort method that accounts for informative censoring, we estimated that, in the absence of breast, ovarian, and pancreatic cancers, and melanoma, female carriers had a life expectancy that was 6.8 years lower (95% CI: 1.2-10.5) than non-carriers. In male mutation carriers, the reduction in life expectancy, in the absence of prostate and pancreatic cancers and melanoma, was 3.7 (95% CI: -0.4, 6.8) years. When deaths and follow-up times after any cancer diagnosis were excluded, the difference in life expectancy was 5.7 years for women (95% CI: -0.1, 10.4) and 3.7 years for men (95% CI: -0.4, 6.9). An overall test of association for men and women together showed a statistically significant association between BRCA1/2 mutations and increased non-cancer mortality (p = 0.024).
CONCLUSIONS/SIGNIFICANCE: These findings suggest that there may be unknown effects of BRCA1/2 mutations on non-neoplastic diseases that cause death at older ages.
尽管对携带BRCA1和BRCA2突变者患乳腺癌、卵巢癌和前列腺癌风险的增加已进行了广泛研究，但其对死亡率的影响尚未得到充分量化。此外，BRCA突变对非癌症死亡风险的可能影响尚未得到研究。
方法/主要发现：在一项针对华盛顿特区地区阿什肯纳兹犹太人群体的社区研究中，我们利用5287名基因分型参与者亲属的死亡率数据（其中120人携带阿什肯纳兹犹太奠基者BRCA突变），研究了三种阿什肯纳兹BRCA奠基者突变与总体和非癌症死亡风险之间的关联。为了研究这些突变既定影响之外的风险，我们分析了排除报告诊断为黑色素瘤以及乳腺癌、卵巢癌、前列腺癌和胰腺癌后的死亡及随访时间的数据。使用考虑信息删失的亲属队列方法扩展版，我们估计，在没有乳腺癌、卵巢癌和胰腺癌以及黑色素瘤的情况下，女性携带者的预期寿命比非携带者低6.8岁（95%置信区间：1.2 - 10.5）。在男性突变携带者中，在没有前列腺癌和胰腺癌以及黑色素瘤的情况下，预期寿命缩短3.7岁（95%置信区间：-0.4, 6.8）。当排除任何癌症诊断后的死亡及随访时间后，女性预期寿命差异为5.7岁（95%置信区间：-0.1, 10.4），男性为3.7岁（95%置信区间：-0.4, 6.9）。对男性和女性的总体关联检验显示，BRCA1/2突变与非癌症死亡率增加之间存在统计学显著关联（p = 0.024）。
结论/意义：这些发现表明，BRCA1/2突变可能对导致老年死亡的非肿瘤性疾病有未知影响。
