A genome-wide association study identifies three novel genetic markers for response to tamoxifen: A prospective multicenter study

Purpose
Although association studies of genetic variations with the clinical outcomes of breast cancer patients treated with tamoxifen have been reported, genetic factors which could determine individual response to tamoxifen are not fully clarified. We performed a genome-wide association study (GWAS) to identify novel genetic markers for response to tamoxifen.
Experimental design
We prospectively collected 347 blood samples from patients with hormone receptor-positive and human epidermal growth factor receptor 2-negative, invasive breast cancer receiving preoperative tamoxifen monotherapy for 14 to 28 days. We used Ki-67 response in breast cancer tissues after preoperative short-term tamoxifen therapy as a surrogate marker for response to tamoxifen. We performed GWAS and genotype imputation using 275 patients, and an independent set of 72 patients was used for replication study.
Results
The combined result of GWAS and the replication study, and subsequent imputation analysis indicated possible association of three loci with Ki-67 response after tamoxifen therapy (rs17198973 on chromosome 4q34.3, rs4577773 on 6q12, and rs7087428 on 10p13, Pcombined = 5.69 x 10−6, 1.64 x 10−5, and 9.77 x 10−6, respectively). When patients were classified into three groups by the scoring system based on the genotypes of the three SNPs, patients with higher scores showed significantly higher after/before ratio of Ki-67 compared to those with lower scores (P = 1.8 x 10−12), suggesting the cumulative effect of the three SNPs.
Conclusion
We identified three novel loci, which could be associated with clinical response to tamoxifen. These findings provide new insights into personalized hormonal therapy for the patients with breast cancer.

目的：尽管已有针对接受他莫昔芬治疗的乳腺癌患者的遗传变异与临床结局的关联研究被报道，但可决定个体对他莫昔芬应答的遗传因素尚未完全阐明。本研究开展全基因组关联研究（Genome-Wide Association Study, GWAS），旨在筛选与他莫昔芬应答相关的新型遗传标志物。
实验设计：本研究前瞻性收集了347份血液样本，受试者均为激素受体阳性、人表皮生长因子受体2（human epidermal growth factor receptor 2, HER2）阴性的浸润性乳腺癌患者，且术前接受为期14至28天的他莫昔芬单药治疗。以术前短期他莫昔芬治疗后乳腺癌组织中的Ki-67应答水平作为他莫昔芬应答的替代标志物。本研究使用275例患者开展全基因组关联研究及基因型填充分析，另有72例独立患者队列用于验证研究。
结果：全基因组关联研究与验证研究的联合分析结果，以及后续的基因型填充分析显示，3个基因座与他莫昔芬治疗后的Ki-67应答存在潜在关联（分别为4q34.3染色体上的rs17198973、6q12染色体上的rs4577773以及10p13染色体上的rs7087428，联合P值分别为5.69×10^-6、1.64×10^-5和9.77×10^-6）。基于这3个单核苷酸多态性（Single Nucleotide Polymorphism, SNP）的基因型构建评分系统，将患者分为3组后，评分较高的患者其Ki-67治疗前后比值显著高于评分较低的患者（P=1.8×10^-12），提示这3个单核苷酸多态性存在累积效应。
结论：本研究筛选出3个新型基因座，其可能与他莫昔芬的临床应答相关。上述研究结果为乳腺癌患者的个体化内分泌治疗提供了新的理论参考。