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

Hiroshi Onishi, Chihiro Udagawa, Michiaki Kubo, Seigo Nakamura, Sadako Akashi-Tanaka, Takashi Kuwayama, Chie Watanabe, Tomoko Takamaru, Hiroyuki Takei, Takashi Ishikawa, Kana Miyahara, Hiroshi Matsumoto, Yoshie Hasegawa, Yukihide Momozawa, Siew Kee Low, Goro Kutomi, Hiroaki Shima, Fukino Satomi, Minoru Okazaki, Hisamitsu ZahaMai Onomura, Ayami Matsukata, Yasuaki Sagara, Shinichi Baba, Akimitsu Yamada, Kazuhiro Shimada, Daisuke Shimizu, Koichiro Tsugawa, Arata Shimo, Mikael Hartman, Ching Wan Chan, Soo Chin Lee, Itaru Endo, Hitoshi Zembutsu

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Abstract

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.

Original languageEnglish
Article numbere0201606
JournalPloS one
Volume13
Issue number8
DOIs
Publication statusPublished - 08-2018

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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