Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, 1-1, Kanokoden, Chikusa-ku, Nagoya 464-8681, Japan.
Breast Cancer Res Treat. 2012 Apr;132(2):711-21. doi: 10.1007/s10549-011-1904-5. Epub 2011 Dec 11.
Genome-wide association studies (GWASs) have identified genetic variants associated with breast cancer. Most GWASs to date have been conducted in women of European descent, however, and the contribution of these variants as predictors in Japanese women is unknown. Here, we analyzed 23 genetic variants identified in previous GWASs and conducted a case-control study with 697 case subjects and 1,394 age- and menopausal status-matched controls. We fit conditional regression models with genetic variants and conventional risk factors. In addition, we created a polygenetic risk score, using those variants with a statistically significant association with breast cancer risk, and also evaluated the contribution of these genetic predictors using the c statistic. Eleven single-nucleotide polymorphisms (SNPs) revealed significant associations with breast cancer risk. A dose-dependent association was observed between the risk of breast cancer and the genetic risk score, which was an aggregate measure of alleles in seven selected variants, namely FGFR2-rs2981579, TOX3/TNRC9-rs3803662, C6orf97-rs2046210, 8q24-rs13281615, SLC4A7-rs4973768, LSP1-rs38137198, and CASP8-rs10931936. Compared to women with scores of 3 or less, odds ratios (ORs) for women with scores of 4-5, 6-7, 8-9, and 10 or more were 1.33 (95% confidence interval, 1.00-1.80), 1.71 (1.26-2.30), 3.01 (1.97-4.58), and 8.69 (2.75-27.5), respectively (P (trend) = 1.9 × 10(-9)). The c statistic for a model including the genetic risk score in addition to the conventional risk factors was 0.6933, versus 0.6652 with the conventional risk factors only (P = 1.3 × 10(-4)). Population-attributable fraction of the risk score was 33.0%. In conclusion, we identified a genetic risk predictor of breast cancer in a Japanese population. Risk models which include a genetic risk score are possibly useful in distinguishing women at high risk of breast cancer from those at low risk, particularly in the context of targeted prevention.
全基因组关联研究（GWAS）已经确定了与乳腺癌相关的遗传变异。迄今为止，大多数 GWAS 都是在欧洲血统的女性中进行的，而这些变异作为日本女性的预测因子的贡献尚不清楚。在这里，我们分析了之前 GWAS 中确定的 23 个遗传变异，并对 697 例病例和 1394 例年龄和绝经状态匹配的对照进行了病例对照研究。我们拟合了带有遗传变异和常规危险因素的条件回归模型。此外，我们使用与乳腺癌风险有统计学显著关联的那些变异创建了一个多基因风险评分，并使用 C 统计量评估了这些遗传预测因子的贡献。11 个单核苷酸多态性（SNP）与乳腺癌风险显著相关。乳腺癌风险与遗传风险评分之间存在剂量依赖性关联，遗传风险评分是七个选定变体中的等位基因的综合测量值，即 FGFR2-rs2981579、TOX3/TNRC9-rs3803662、C6orf97-rs2046210、8q24-rs13281615、SLC4A7-rs4973768、LSP1-rs38137198 和 CASP8-rs10931936。与评分在 3 或以下的女性相比，评分在 4-5、6-7、8-9 和 10 或更高的女性的比值比（OR）分别为 1.33（95%置信区间，1.00-1.80）、1.71（1.26-2.30）、3.01（1.97-4.58）和 8.69（2.75-27.5）（P(trend)=1.9×10(-9)）。在常规危险因素之外还包括遗传风险评分的模型的 C 统计量为 0.6933，而仅包括常规危险因素的模型为 0.6652（P=1.3×10(-4)）。风险评分的人群归因分数为 33.0%。总之，我们在日本人群中确定了乳腺癌的遗传风险预测因子。包含遗传风险评分的风险模型可能有助于区分高风险和低风险的乳腺癌女性，特别是在靶向预防的背景下。
