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 Zaha & 14 others Mai 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

Research output: Contribution to journalArticle

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 - 01-08-2018

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tamoxifen
Genome-Wide Association Study
Tamoxifen
prospective studies
Genetic Markers
Multicenter Studies
Genes
Prospective Studies
genetic markers
breast neoplasms
Breast Neoplasms
therapeutics
Single Nucleotide Polymorphism
Genotype
loci
genome-wide association study
genotype
hormone receptors
Chromosomes
Design of experiments

All Science Journal Classification (ASJC) codes

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

Cite this

Onishi, Hiroshi ; Udagawa, Chihiro ; Kubo, Michiaki ; Nakamura, Seigo ; Akashi-Tanaka, Sadako ; Kuwayama, Takashi ; Watanabe, Chie ; Takamaru, Tomoko ; Takei, Hiroyuki ; Ishikawa, Takashi ; Miyahara, Kana ; Matsumoto, Hiroshi ; Hasegawa, Yoshie ; Momozawa, Yukihide ; Low, Siew Kee ; Kutomi, Goro ; Shima, Hiroaki ; Satomi, Fukino ; Okazaki, Minoru ; Zaha, Hisamitsu ; Onomura, Mai ; Matsukata, Ayami ; Sagara, Yasuaki ; Baba, Shinichi ; Yamada, Akimitsu ; Shimada, Kazuhiro ; Shimizu, Daisuke ; Tsugawa, Koichiro ; Shimo, Arata ; Hartman, Mikael ; Chan, Ching Wan ; Lee, Soo Chin ; Endo, Itaru ; Zembutsu, Hitoshi. / A genome-wide association study identifies three novel genetic markers for response to tamoxifen : A prospective multicenter study. In: PloS one. 2018 ; Vol. 13, No. 8.
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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.",
author = "Hiroshi Onishi and Chihiro Udagawa and Michiaki Kubo and Seigo Nakamura and Sadako Akashi-Tanaka and Takashi Kuwayama and Chie Watanabe and Tomoko Takamaru and Hiroyuki Takei and Takashi Ishikawa and Kana Miyahara and Hiroshi Matsumoto and Yoshie Hasegawa and Yukihide Momozawa and Low, {Siew Kee} and Goro Kutomi and Hiroaki Shima and Fukino Satomi and Minoru Okazaki and Hisamitsu Zaha and Mai Onomura and Ayami Matsukata and Yasuaki Sagara and Shinichi Baba and Akimitsu Yamada and Kazuhiro Shimada and Daisuke Shimizu and Koichiro Tsugawa and Arata Shimo and Mikael Hartman and Chan, {Ching Wan} and Lee, {Soo Chin} and Itaru Endo and Hitoshi Zembutsu",
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Onishi, H, Udagawa, C, Kubo, M, Nakamura, S, Akashi-Tanaka, S, Kuwayama, T, Watanabe, C, Takamaru, T, Takei, H, Ishikawa, T, Miyahara, K, Matsumoto, H, Hasegawa, Y, Momozawa, Y, Low, SK, Kutomi, G, Shima, H, Satomi, F, Okazaki, M, Zaha, H, Onomura, M, Matsukata, A, Sagara, Y, Baba, S, Yamada, A, Shimada, K, Shimizu, D, Tsugawa, K, Shimo, A, Hartman, M, Chan, CW, Lee, SC, Endo, I & Zembutsu, H 2018, 'A genome-wide association study identifies three novel genetic markers for response to tamoxifen: A prospective multicenter study' PloS one, vol. 13, no. 8, e0201606. https://doi.org/10.1371/journal.pone.0201606

A genome-wide association study identifies three novel genetic markers for response to tamoxifen : A prospective multicenter study. / Onishi, Hiroshi; Udagawa, Chihiro; Kubo, Michiaki; Nakamura, Seigo; Akashi-Tanaka, Sadako; Kuwayama, Takashi; Watanabe, Chie; Takamaru, Tomoko; Takei, Hiroyuki; Ishikawa, Takashi; Miyahara, Kana; Matsumoto, Hiroshi; Hasegawa, Yoshie; Momozawa, Yukihide; Low, Siew Kee; Kutomi, Goro; Shima, Hiroaki; Satomi, Fukino; Okazaki, Minoru; Zaha, Hisamitsu; Onomura, Mai; Matsukata, Ayami; Sagara, Yasuaki; Baba, Shinichi; Yamada, Akimitsu; Shimada, Kazuhiro; Shimizu, Daisuke; Tsugawa, Koichiro; Shimo, Arata; Hartman, Mikael; Chan, Ching Wan; Lee, Soo Chin; Endo, Itaru; Zembutsu, Hitoshi.

In: PloS one, Vol. 13, No. 8, e0201606, 01.08.2018.

Research output: Contribution to journalArticle

TY - JOUR

T1 - A genome-wide association study identifies three novel genetic markers for response to tamoxifen

T2 - A prospective multicenter study

AU - Onishi, Hiroshi

AU - Udagawa, Chihiro

AU - Kubo, Michiaki

AU - Nakamura, Seigo

AU - Akashi-Tanaka, Sadako

AU - Kuwayama, Takashi

AU - Watanabe, Chie

AU - Takamaru, Tomoko

AU - Takei, Hiroyuki

AU - Ishikawa, Takashi

AU - Miyahara, Kana

AU - Matsumoto, Hiroshi

AU - Hasegawa, Yoshie

AU - Momozawa, Yukihide

AU - Low, Siew Kee

AU - Kutomi, Goro

AU - Shima, Hiroaki

AU - Satomi, Fukino

AU - Okazaki, Minoru

AU - Zaha, Hisamitsu

AU - Onomura, Mai

AU - Matsukata, Ayami

AU - Sagara, Yasuaki

AU - Baba, Shinichi

AU - Yamada, Akimitsu

AU - Shimada, Kazuhiro

AU - Shimizu, Daisuke

AU - Tsugawa, Koichiro

AU - Shimo, Arata

AU - Hartman, Mikael

AU - Chan, Ching Wan

AU - Lee, Soo Chin

AU - Endo, Itaru

AU - Zembutsu, Hitoshi

PY - 2018/8/1

Y1 - 2018/8/1

N2 - 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.

AB - 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.

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DO - 10.1371/journal.pone.0201606

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