Susanne Levy Gertner Oncogenetics Unit, Institute of Human Genetics, The Chaim Sheba Medical Center, Tel-Hashomer, Israel.
Int J Cancer. 2010 Aug 1;127(3):589-97. doi: 10.1002/ijc.25065.
We hypothesized that aberrant gene silencing by miRNA may affect mutant BRCA penetrance. To test this notion, frequency of single nucleotide polymorphisms (SNPs; n = 42) within predicted miRNA binding sites or miRNA precursors were determined and compared in 363 BRCA1 mutation carriers: asymptomatic (n = 160), breast cancer (n = 140) and ovarian cancer (n = 63) patients, and in 125 BRCA2 mutation carriers: asymptomatic (n = 48), breast cancer (n = 58) and ovarian cancer (n = 19) patients. Overall, 16 of 42 SNPs were polymorphic, 11 had a minor allele frequency greater than 5% and 9 of them maintained the Hardy-Weinberg Equilibrium. Based on Cox regression and Kaplan-Meier analyses, statistically significant differences were noted in BRCA2 mutation carriers by health status in 3 SNPs: CC homozygosity at rs6505162 increased ovarian cancer risk (RR 2.77; p = 0.028; 95% CI, 1.11-6.9); heterozygote SNP carriers of rs11169571 had an approximately 2 fold increased risk for developing breast/ovarian cancer, whereas heterozygotes of the rs895819 SNP had an approximately 50% reduced risk for developing breast/ovarian cancer. This study provides preliminary evidence for another regulatory level of penetrance of deleterious mutations in cancer predisposition genes.
我们假设 miRNA 导致的异常基因沉默可能会影响突变 BRCA 的外显率。为了验证这一观点，我们检测并比较了 363 名 BRCA1 突变携带者（无症状者 160 名，乳腺癌患者 140 名，卵巢癌患者 63 名）和 125 名 BRCA2 突变携带者（无症状者 48 名，乳腺癌患者 58 名，卵巢癌患者 19 名）中预测的 miRNA 结合位点或 miRNA 前体中的单核苷酸多态性（SNP；n=42）的频率。总体而言，42 个 SNP 中有 16 个是多态性的，11 个具有大于 5%的次要等位基因频率，其中 9 个符合 Hardy-Weinberg 平衡。基于 Cox 回归和 Kaplan-Meier 分析，在 BRCA2 突变携带者中，3 个 SNP 的健康状况存在统计学显著差异：rs6505162 的 CC 纯合性增加了卵巢癌风险（RR 2.77；p=0.028；95%CI，1.11-6.9）；rs11169571 的杂合子 SNP 携带者患乳腺癌/卵巢癌的风险增加了约 2 倍，而 rs895819 杂合子携带者患乳腺癌/卵巢癌的风险降低了约 50%。本研究为癌症易感性基因中有害突变外显率的另一个调控水平提供了初步证据。
