Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
Hum Mol Genet. 2010 Jul 15;19(14):2886-97. doi: 10.1093/hmg/ddq174. Epub 2010 Apr 23.
Recent studies have identified single nucleotide polymorphisms (SNPs) that significantly modify breast cancer risk in BRCA1 and BRCA2 mutation carriers. Since these risk modifiers were originally identified as genetic risk factors for breast cancer in genome-wide association studies (GWASs), additional risk modifiers for BRCA1 and BRCA2 may be identified from promising signals discovered in breast cancer GWAS. A total of 350 SNPs identified as candidate breast cancer risk factors (P < 1 x 10(-3)) in two breast cancer GWAS studies were genotyped in 3451 BRCA1 and 2006 BRCA2 mutation carriers from nine centers. Associations with breast cancer risk were assessed using Cox models weighted for penetrance. Eight SNPs in BRCA1 carriers and 12 SNPs in BRCA2 carriers, representing an enrichment over the number expected, were significantly associated with breast cancer risk (P(trend) < 0.01). The minor alleles of rs6138178 in SNRPB and rs6602595 in CAMK1D displayed the strongest associations in BRCA1 carriers (HR = 0.78, 95% CI: 0.69-0.90, P(trend) = 3.6 x 10(-4) and HR = 1.25, 95% CI: 1.10-1.41, P(trend) = 4.2 x 10(-4)), whereas rs9393597 in LOC134997 and rs12652447 in FBXL7 showed the strongest associations in BRCA2 carriers (HR = 1.55, 95% CI: 1.25-1.92, P(trend) = 6 x 10(-5) and HR = 1.37, 95% CI: 1.16-1.62, P(trend) = 1.7 x 10(-4)). The magnitude and direction of the associations were consistent with the original GWAS. In subsequent risk assessment studies, the loci appeared to interact multiplicatively for breast cancer risk in BRCA1 and BRCA2 carriers. Promising candidate SNPs from GWAS were identified as modifiers of breast cancer risk in BRCA1 and BRCA2 carriers. Upon further validation, these SNPs together with other genetic and environmental factors may improve breast cancer risk assessment in these populations.
最近的研究已经确定了单核苷酸多态性 (SNPs)，这些 SNP 显著改变了 BRCA1 和 BRCA2 突变携带者的乳腺癌风险。由于这些风险修饰因子最初是在全基因组关联研究 (GWAS) 中作为乳腺癌的遗传风险因子被发现的，因此，在乳腺癌 GWAS 中发现的有前途的信号中，可能会发现更多的 BRCA1 和 BRCA2 的风险修饰因子。在来自 9 个中心的 3451 名 BRCA1 和 2006 名 BRCA2 突变携带者中，对两项乳腺癌 GWAS 研究中确定的 350 个候选乳腺癌风险因子（P < 1 x 10(-3)) 的 SNP 进行了基因分型。使用加权穿透性的 Cox 模型评估与乳腺癌风险的关联。在 BRCA1 携带者中有 8 个 SNP 和 BRCA2 携带者中有 12 个 SNP 与乳腺癌风险显著相关（P(trend) < 0.01）。在 BRCA1 携带者中，SNRPB 中的 rs6138178 和 CAMK1D 中的 rs6602595 的次要等位基因显示出最强的关联（HR = 0.78，95%CI：0.69-0.90，P(trend) = 3.6 x 10(-4) 和 HR = 1.25，95%CI：1.10-1.41，P(trend) = 4.2 x 10(-4)），而在 BRCA2 携带者中，LOC134997 中的 rs9393597 和 FBXL7 中的 rs12652447 显示出最强的关联（HR = 1.55，95%CI：1.25-1.92，P(trend) = 6 x 10(-5) 和 HR = 1.37，95%CI：1.16-1.62，P(trend) = 1.7 x 10(-4)）。关联的大小和方向与原始 GWAS 一致。在随后的风险评估研究中，这些位点似乎在 BRCA1 和 BRCA2 携带者的乳腺癌风险中具有乘法交互作用。来自 GWAS 的有前途的候选 SNP 被确定为 BRCA1 和 BRCA2 携带者乳腺癌风险的修饰因子。经过进一步验证，这些 SNP 以及其他遗传和环境因素可能会改善这些人群的乳腺癌风险评估。
