Genetic Epidemiology and Bioinformatics Research Group, Human Genetics Research Division, University of Southampton School of Medicine, Southampton General Hospital, United Kingdom.
Cancer Res. 2013 Mar 15;73(6):1883-91. doi: 10.1158/0008-5472.CAN-12-3377. Epub 2013 Jan 14.
Genome-Wide Association Studies (GWAS) have begun to investigate associations between inherited genetic variations and breast cancer prognosis. Here, we report our findings from a GWAS conducted in 536 patients with early-onset breast cancer aged 40 or less at diagnosis and with a mean follow-up period of 4.1 years (SD = 1.96). Patients were selected from the Prospective Study of Outcomes in Sporadic versus Hereditary breast cancer. A Bonferroni correction for multiple testing determined that a P value of 1.0 × 10(-7) was a statistically significant association signal. Following quality control, we identified 487,496 single nucleotide polymorphisms (SNP) for association tests in stage 1. In stage 2, 35 SNPs with the most significant associations were genotyped in 1,516 independent cases from the same early-onset cohort. In stage 2, 11 SNPs remained associated in the same direction (P ≤ 0.05). Fixed effects meta-analysis models identified one SNP associated at close to genome wide level of significance 556 kb upstream of the ARRDC3 locus [HR = 1.61; 95% confidence interval (CI), 1.33-1.96; P = 9.5 × 10(-7)]. Four further associations at or close to the PBX1, RORα, NTN1, and SYT6 loci also came close to genome-wide significance levels (P = 10(-6)). In the first ever GWAS for the identification of SNPs associated with prognosis in patients with early-onset breast cancer, we report a SNP upstream of the ARRDC3 locus as potentially associated with prognosis (median follow-up time for genotypes: CC = 4 years, CT = 3 years, and TT = 2.7 years; Wilcoxon rank-sum test CC vs. CT, P = 4 × 10(-4) and CT vs. TT, P = 0.76). Four further loci may also be associated with prognosis.
全基因组关联研究（GWAS）已开始研究遗传变异与乳腺癌预后之间的关联。在这里，我们报告了在 536 名 40 岁或以下确诊为早期乳腺癌且平均随访时间为 4.1 年（SD=1.96）的患者中进行的 GWAS 的发现。这些患者来自于散发性与遗传性乳腺癌的前瞻性研究。对多次检验进行 Bonferroni 校正后，确定 P 值为 1.0×10(-7)是具有统计学意义的关联信号。经过质量控制，我们在第一阶段确定了 487,496 个单核苷酸多态性（SNP）进行关联测试。在第二阶段，在来自同一早期发病队列的 1,516 例独立病例中对 35 个具有最显著关联的 SNP 进行了基因分型。在第二阶段，11 个 SNP 仍然呈相同方向的关联（P≤0.05）。固定效应荟萃分析模型确定了一个 SNP 与 ARRDC3 基因座上游约 556kb 处接近全基因组水平的显著性相关[风险比（HR）=1.61；95%置信区间（CI），1.33-1.96；P=9.5×10(-7)]。位于 PBX1、RORα、NTN1 和 SYT6 基因座的另外四个关联也接近全基因组显著水平（P=10(-6)）。在首次针对早期乳腺癌患者预后相关 SNP 的 GWAS 中，我们报告了 ARRDC3 基因座上游的一个 SNP 可能与预后相关（基因型的中位随访时间：CC=4 年，CT=3 年，TT=2.7 年；Wilcoxon 秩和检验 CC 与 CT，P=4×10(-4)；CT 与 TT，P=0.76）。另外四个基因座也可能与预后相关。
