Department of Public Health Sciences, University of Chicago, Chicago, Illinois.
University of Illinois at Chicago, Chicago, Illinois.
Cancer Epidemiol Biomarkers Prev. 2018 Sep;27(9):1057-1064. doi: 10.1158/1055-9965.EPI-17-1185. Epub 2018 Jun 13.
Although germline genetics influences breast cancer incidence, published research only explains approximately half of the expected association. Moreover, the accuracy of prediction models remains low. For women who develop breast cancer early, the genetic architecture is less established. To identify loci associated with early-onset breast cancer, gene-based tests were carried out using exome array data from 3,479 women with breast cancer diagnosed before age 50 and 973 age-matched controls. Replication was undertaken in a population that developed breast cancer at all ages of onset. Three gene regions were associated with breast cancer incidence: ( = 1.23 × 10; replication < 1.00 × 10), ( = 3.57 × 10; replication < 1.00 × 10), and ( = 5.49 × 10; replication < 1.00 × 10). Of the 151 gene regions reported in previous literature, 19 (12.5%) showed evidence of association ( < 0.05) with the risk of early-onset breast cancer in the early-onset population. To predict incidence, whole-genome prediction was implemented on a subset of 3,076 participants who were additionally genotyped on a genome wide array. The whole-genome prediction outperformed a polygenic risk score [AUC, 0.636; 95% confidence interval (CI), 0.614-0.659 compared with 0.601; 95% CI, 0.578-0.623], and when combined with known epidemiologic risk factors, the AUC rose to 0.662 (95% CI, 0.640-0.684). This research supports a role for variation within and in breast cancer incidence, and suggests as a novel risk locus. This analysis supports a shared genetic etiology between women with early- and late-onset breast cancer, and suggests whole-genome data can improve risk assessment. .
尽管种系遗传学影响乳腺癌的发病率，但已发表的研究仅能解释预期关联的大约一半。此外，预测模型的准确性仍然较低。对于那些较早发生乳腺癌的女性，其遗传结构尚未确定。为了确定与早发性乳腺癌相关的基因座，使用来自 3479 名 50 岁以下诊断为乳腺癌的女性和 973 名年龄匹配对照者的外显子组阵列数据进行了基于基因的测试。在所有发病年龄均发生乳腺癌的人群中进行了复制研究。三个基因区域与乳腺癌发病率相关：（ = 1.23 × 10；复制 ＜ 1.00 × 10），（ = 3.57 × 10；复制 ＜ 1.00 × 10）和（ = 5.49 × 10；复制 ＜ 1.00 × 10）。在之前文献中报告的 151 个基因区域中，有 19 个（12.5%）在早发性人群中显示出与早发性乳腺癌风险相关的证据（＜0.05）。为了预测发病风险，对另外还进行了全基因组基因分型的 3076 名参与者的子集中实施了全基因组预测。全基因组预测的表现优于多基因风险评分 [AUC，0.636；95%置信区间（CI），0.614-0.659 与 0.601；95%CI，0.578-0.623]，当与已知的流行病学风险因素结合时，AUC 升高至 0.662（95%CI，0.640-0.684）。这项研究支持 和 内的变异在乳腺癌发病率中的作用，并提示 是一个新的风险基因座。该分析支持早发和晚发乳腺癌女性之间存在共同的遗传病因，并提示全基因组数据可以改善风险评估。
