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A Genome-Wide Association Study Identifies Five Novel Genetic Markers for Trastuzumab-Induced Cardiotoxicity in Japanese Population.
Nakano, Mari Hara; Udagawa, Chihiro; Shimo, Arata; Kojima, Yasuyuki; Yoshie, Reiko; Zaha, Hisamitsu; Abe, Norie; Motonari, Tokiwa; Unesoko, Mikiko; Tamura, Kenji; Shimoi, Tatsunori; Yoshida, Masayuki; Yoshida, Teruhiko; Sakamoto, Hiromi; Kato, Ken; Mushiroda, Taisei; Tsugawa, Koichiro; Zembutsu, Hitoshi.
Afiliação
  • Nakano MH; Project for Development of Liquid Biopsy Diagnosis, Japanese Foundation for Cancer Research, Research Institute.
  • Udagawa C; Division of Breast and Endocrine Surgery, Department of Surgery, St.Marianna University School of Medicine.
  • Shimo A; Project for Development of Liquid Biopsy Diagnosis, Japanese Foundation for Cancer Research, Research Institute.
  • Kojima Y; New Business Development Life Science Group, Toyo Kohan Co., Ltd.
  • Yoshie R; Division of Breast and Endocrine Surgery, Department of Surgery, St.Marianna University School of Medicine.
  • Zaha H; Division of Breast and Endocrine Surgery, Department of Surgery, St.Marianna University School of Medicine.
  • Abe N; Division of Breast and Endocrine Surgery, Department of Surgery, St.Marianna University School of Medicine.
  • Motonari T; Department of Breast Surgery, Nakagami Hospital.
  • Unesoko M; Department of Breast Surgery, Nakagami Hospital.
  • Tamura K; Department of Breast Surgery, Nakagami Hospital.
  • Shimoi T; Department of Breast Surgery, Nakagami Hospital.
  • Yoshida M; Department of Breast and Medical Oncology, National Cancer Center Hospital.
  • Yoshida T; Department of Breast and Medical Oncology, National Cancer Center Hospital.
  • Sakamoto H; Department of Pathology and Clinical Laboratories, National Cancer Center Hospital.
  • Kato K; Fundamental Innovative Oncology Core, National Cancer Center Research Institute.
  • Mushiroda T; Fundamental Innovative Oncology Core, National Cancer Center Research Institute.
  • Tsugawa K; Department of Gastrointestinal Medical Oncology, National Cancer Center Hospital.
  • Zembutsu H; RIKEN, Center for Integrative Medical Sciences.
Biol Pharm Bull ; 42(12): 2045-2053, 2019 Dec 01.
Article em En | MEDLINE | ID: mdl-31597885
ABSTRACT
Trastuzumab has been administered to patients with human epidermal growth factor receptor 2 (HER2)-positive cancer, however, the cardiotoxicity is identified as one of the life-threatening toxicities. Clinically useful biomarker for trastuzumab-induced cardiotoxicity has been expected to be developed. To identify a novel genetic marker(s) determining the risk of trastuzumab-induced cardiotoxicity, we performed a first genome-wide association study (GWAS) in Japanese population. We enrolled 481 patients who had been treated with trastuzumab and carried out a GWAS using 11 cases (with cardiotoxicity) and 257 controls (without cardiotoxicity). Top 100 single nucleotide polymorphisms (SNPs) which revealed the smallest p values in GWAS (p = 7.60 × 10-7 - 2.01 × 10-4) were further examined using replication samples consisted of 14 cases and 199 controls. The combined analysis of the GWAS and replication study indicated possible association of five loci with trastuzumab-induced cardiotoxicity (rs9316695 on chromosome 13q14.3, rs28415722 on chromosome 15q26.3, rs7406710 on chromosome 17q25.3, rs11932853 on chromosome 4q25, and rs8032978 on chromosome 15q26.3, Pcombined = 6.00 × 10-6, 8.88 × 10-5, 1.07 × 10-4, 1.42 × 10-4, 1.60 × 10-4, respectively). Furthermore, we developed a risk prediction model for trastuzumab-induced cardiotoxicity using the five marker SNPs. The incidence of trastuzumab-induced cardiotoxicity in patients with risk score ≥5 was significantly higher (42.5%) compared to that in patients with score ≤ 4 (1.8%) (p = 7.82 × 10-15, odds ratio = 40.0). These findings suggest the potential to improve the ability of physicians to avoid the trastuzumab-induced cardiotoxicity for patients with HER2-positive cancer.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Neoplasias da Mama / Cardiotoxicidade / Trastuzumab Tipo de estudo: Etiology_studies / Prognostic_studies / Risk_factors_studies Limite: Adult / Aged / Aged80 / Female / Humans / Male / Middle aged País/Região como assunto: Asia Idioma: En Revista: Biol Pharm Bull Assunto da revista: BIOQUIMICA / FARMACOLOGIA Ano de publicação: 2019 Tipo de documento: Article País de publicação: JAPAN / JAPON / JAPÃO / JP

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Neoplasias da Mama / Cardiotoxicidade / Trastuzumab Tipo de estudo: Etiology_studies / Prognostic_studies / Risk_factors_studies Limite: Adult / Aged / Aged80 / Female / Humans / Male / Middle aged País/Região como assunto: Asia Idioma: En Revista: Biol Pharm Bull Assunto da revista: BIOQUIMICA / FARMACOLOGIA Ano de publicação: 2019 Tipo de documento: Article País de publicação: JAPAN / JAPON / JAPÃO / JP