BRCA2 Polymorphic Stop Codon K3326X and the Risk of Breast, Prostate, and Ovarian Cancers
BRCA2 Polymorphic Stop Codon K3326X and the Risk of Breast, Prostate, and Ovarian Cancers
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DOI：
10.1093/jnci/djv315
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发表时间：
2016-02-01
影响因子：
10.3
通讯作者：
Goldgar, David E.
中科院分区：
文献类型：
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作者：
Meeks, Huong D.;Song, Honglin;Goldgar, David E.
背景：BRCA2 中的 K3326X 变异（BRCA2*c.9976A>T；p.Lys3326*；rs11571833）已被发现与乳腺癌风险小幅增加相关。然而，尚不清楚连锁不平衡与完全致病性突变在多大程度上可以解释这种关联。关于 K3326X 在其他激素相关癌症中的作用的信息很少。方法：使用加权逻辑回归，我们分析了大型 iCOGS 研究的数据，包括 76 637 名癌症病例患者和 83 796 名对照患者，以估计 K3326X 变异携带者与乳腺癌、卵巢癌和前列腺癌风险相关的比值比 (ORw) 和 95% 置信区间 (CI)，权重定义为不具有致病性的概率BRCA2 变体。使用 Cox 比例风险模型，我们还检查了 7183 名 BRCA1 变异携带者中 K3326X 与乳腺癌和卵巢癌风险的关联。所有统计检验均为双边。结果：K3326X 变异与乳腺癌（ORw = 1.28，95% CI = 1.17 至 1.40，P = 5.9x10(-6)）和浸润性卵巢癌（ORw = 1.26，95% CI = 1.10 至 1.43，P = 3.8x10(-3)）相关。这些关联在浆液性卵巢癌和雌激素受体阴性乳腺癌中更为明显（分别为 ORw = 1.46，95% CI = 1.2 至 1.70，P = 3.4x10(-5) 和 ORw = 1.50，95% CI = 1.28 至 1.76，P = 4.1x10(-5)）。对于 BRCA1 突变携带者，K3326X 变异与卵巢癌风险呈显着负相关（HR = 0.43，95% CI = 0.22 至 0.84，P = 0.013），但与乳腺癌无关。未观察到与前列腺癌的关联。结论：我们的研究提供的证据表明，K3326X 变异与患乳腺癌和卵巢癌的风险相关，独立于 BRCA2 中的其他致病变异。需要进一步的研究来确定造成这些关联的生物学作用机制。
Background: The K3326X variant in BRCA2 (BRCA2*c.9976A>T; p.Lys3326*; rs11571833) has been found to be associated with small increased risks of breast cancer. However, it is not clear to what extent linkage disequilibrium with fully pathogenic mutations might account for this association. There is scant information about the effect of K3326X in other hormone-related cancers.Methods: Using weighted logistic regression, we analyzed data from the large iCOGS study including 76 637 cancer case patients and 83 796 control patients to estimate odds ratios (ORw) and 95% confidence intervals (CIs) for K3326X variant carriers in relation to breast, ovarian, and prostate cancer risks, with weights defined as probability of not having a pathogenic BRCA2 variant. Using Cox proportional hazards modeling, we also examined the associations of K3326X with breast and ovarian cancer risks among 7183 BRCA1 variant carriers. All statistical tests were two-sided.Results: The K3326X variant was associated with breast (ORw = 1.28, 95% CI = 1.17 to 1.40, P = 5.9x10(-6)) and invasive ovarian cancer (ORw = 1.26, 95% CI = 1.10 to 1.43, P = 3.8x10(-3)). These associations were stronger for serous ovarian cancer and for estrogen receptor-negative breast cancer (ORw = 1.46, 95% CI = 1.2 to 1.70, P = 3.4x10(-5) and ORw = 1.50, 95% CI = 1.28 to 1.76, P = 4.1x10(-5), respectively). For BRCA1 mutation carriers, there was a statistically significant inverse association of the K3326X variant with risk of ovarian cancer (HR = 0.43, 95% CI = 0.22 to 0.84, P = .013) but no association with breast cancer. No association with prostate cancer was observed.Conclusions: Our study provides evidence that the K3326X variant is associated with risk of developing breast and ovarian cancers independent of other pathogenic variants in BRCA2. Further studies are needed to determine the biological mechanism of action responsible for these associations.