title: Association of variations in HLA class II and other loci with susceptibility to EGFR-mutated lung adenocarcinoma.
abstract: Lung adenocarcinoma driven by somatic EGFR mutations is more prevalent in East Asians (30-50%) than in European/Americans (10-20%). Here we investigate genetic factors underlying the risk of this disease by conducting a genome-wide association study, followed by two validation studies, in 3,173 Japanese patients with EGFR mutation-positive lung adenocarcinoma and 15,158 controls. Four loci, 5p15.33 (TERT), 6p21.3 (BTNL2), 3q28 (TP63) and 17q24.2 (BPTF), previously shown to be strongly associated with overall lung adenocarcinoma risk in East Asians, were re-discovered as loci associated with a higher susceptibility to EGFR mutation-positive lung adenocarcinoma. In addition, two additional loci, HLA class II at 6p21.32 (rs2179920; P =5.1 × 10(-17), per-allele OR=1.36) and 6p21.1 (FOXP4) (rs2495239; P=3.9 × 10(-9), per-allele OR=1.19) were newly identified as loci associated with EGFR mutation-positive lung adenocarcinoma. This study indicates that multiple genetic factors underlie the risk of lung adenocarcinomas with EGFR mutations.
authors: Division of Genome Biology, National Cancer Center Research Institute, Tokyo 104-0045, Japan.
authors: Kouya
authors: K
authors: Shiraishi
authors: Department of Human Genetics and Disease Diversity, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.|Department of Statistical Genetics, Osaka University Graduate School of Medicine, Yokohama 230-0045, Japan.|Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan.
authors: Yukinori
authors: Y
authors: Okada
authors: Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan.|Omics Research Center, National Cerebral and Cardiovascular Center, Osaka 565-8565, Japan.
authors: Atsushi
authors: A
authors: Takahashi
authors: Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan.
authors: Yoichiro
authors: Y
authors: Kamatani
authors: Laboratory for Genotyping Development, Center for Integrative Medical Sciences, RIKEN, Yokohama 113-8510, Japan.
authors: Yukihide
authors: Y
authors: Momozawa
authors: Laboratory for Genotyping Development, Center for Integrative Medical Sciences, RIKEN, Yokohama 113-8510, Japan.
authors: Kyota
authors: K
authors: Ashikawa
authors: Department of Medical Oncology, Japanese Red Cross Medical Center, Tokyo 150-0012, Japan.
authors: Hideo
authors: H
authors: Kunitoh
authors: Division of Translational Research, Exploratory Oncology Research and Clinical Trial Center (EPOC), National Cancer Center Research Institute, Chiba 277-0882, Japan.
authors: Shingo
authors: S
authors: Matsumoto
authors: Center for Antibody and Vaccine Therapy, Research Hospital, Institute of Medical Science, The University of Tokyo, Tokyo 108-0071, Japan.|Department of Medical Oncology and Cancer Center, Shiga University of Medical Science, Otsu 520-2121, Japan.
authors: Atsushi
authors: A
authors: Takano
authors: Department of Integrative Center of General Surgery, Gunma University Hospital, Gunma 371-8511, Japan.
authors: Kimihiro
authors: K
authors: Shimizu
authors: Department of Cellular and Organ Pathology, Graduate School of Medicine, Akita University, Akita 010-8543, Japan.
authors: Akiteru
authors: A
authors: Goto
authors: Department of Pathology, National Cancer Center Hospital, Tokyo 104-0045, Japan.|Department of Pathology and Laboratory Medicine, Kansai Medical University, Osaka 573-1010, Japan.
authors: Koji
authors: K
authors: Tsuta
authors: Division of Thoracic Surgery, National Cancer Centre Hospital, Tokyo 104-0045, Japan.
authors: Shun-Ichi
authors: SI
authors: Watanabe
authors: Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo 104-0045, Japan.
authors: Yuichiro
authors: Y
authors: Ohe
authors: Division of Thoracic Surgery, National Cancer Centre Hospital, Tokyo 104-0045, Japan.
authors: Yukio
authors: Y
authors: Watanabe
authors: Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo 104-0045, Japan.
authors: Yasushi
authors: Y
authors: Goto
authors: Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo 104-0045, Japan.
authors: Hiroshi
authors: H
authors: Nokihara
authors: Department of Clinical Laboratories, National Cancer Center Hospital, Tokyo 104-0045, Japan.|Division of Clinical Laboratory, Kanagawa Cancer Center, Kanagawa 241-0815, Japan.
authors: Koh
authors: K
authors: Furuta
authors: Department of Pathology, National Cancer Center Hospital, Tokyo 104-0045, Japan.
authors: Akihiko
authors: A
authors: Yoshida
authors: Department of Thoracic Oncology, National Cancer Center Hospital East, Chiba 277-0882, Japan.
authors: Koichi
authors: K
authors: Goto
authors: Department of Thoracic Surgery, National Cancer Center Hospital East, Chiba 277-0882, Japan.
authors: Tomoyuki
authors: T
authors: Hishida
authors: Department of Thoracic Surgery, National Cancer Center Hospital East, Chiba 277-0882, Japan.
authors: Masahiro
authors: M
authors: Tsuboi
authors: Division of Translational Research, Exploratory Oncology Research and Clinical Trial Center (EPOC), National Cancer Center Research Institute, Chiba 277-0882, Japan.
authors: Katsuya
authors: K
authors: Tsuchihara
authors: Molecular Pathology and Genetics Division, Kanagawa Cancer Center Research Institute, Kanagawa 241-0815, Japan.
authors: Yohei
authors: Y
authors: Miyagi
authors: Department of Thoracic Surgery, Kanagawa Cancer Center, Kanagawa 241-0815, Japan.
authors: Haruhiko
authors: H
authors: Nakayama
authors: Department of Pathology, Kanagawa Cancer Center, Kanagawa 241-0815, Japan.
authors: Tomoyuki
authors: T
authors: Yokose
authors: Department of Integrative Center of General Surgery, Gunma University Hospital, Gunma 371-8511, Japan.
authors: Kazumi
authors: K
authors: Tanaka
authors: Department of Integrative Center of General Surgery, Gunma University Hospital, Gunma 371-8511, Japan.
authors: Toshiteru
authors: T
authors: Nagashima
authors: Department of Integrative Center of General Surgery, Gunma University Hospital, Gunma 371-8511, Japan.
authors: Yoichi
authors: Y
authors: Ohtaki
authors: Department of Cellular and Organ Pathology, Graduate School of Medicine, Akita University, Akita 010-8543, Japan.
authors: Daichi
authors: D
authors: Maeda
authors: Department of Thoracic Surgery, Graduate School of Medicine, Akita University, Akita 010-8543, Japan.
authors: Kazuhiro
authors: K
authors: Imai
authors: Department of Thoracic Surgery, Graduate School of Medicine, Akita University, Akita 010-8543, Japan.
authors: Yoshihiro
authors: Y
authors: Minamiya
authors: Division of Genetics, National Cancer Center Research Institute, Tokyo 104-0045, Japan.
authors: Hiromi
authors: H
authors: Sakamoto
authors: StaGen Co., Ltd., Tokyo 111-0051, Japan.
authors: Akira
authors: A
authors: Saito
authors: Division of Genome Biology, National Cancer Center Research Institute, Tokyo 104-0045, Japan.
authors: Yoko
authors: Y
authors: Shimada
authors: Division of Genome Biology, National Cancer Center Research Institute, Tokyo 104-0045, Japan.|Department of Clinical Laboratories, National Cancer Center Hospital, Tokyo 104-0045, Japan.
authors: Kuniko
authors: K
authors: Sunami
authors: Division of Genome Biology, National Cancer Center Research Institute, Tokyo 104-0045, Japan.
authors: Motonobu
authors: M
authors: Saito
authors: Department of Molecular Cytogenetics, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.|Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.|Bioresource Research Center, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.
authors: Johji
authors: J
authors: Inazawa
authors: Department of Medicine and Department of Surgery, Center for Personalized Therapeutics, The University of Chicago, Chicago 60637, USA.
authors: Yusuke
authors: Y
authors: Nakamura
authors: Division of Genetics, National Cancer Center Research Institute, Tokyo 104-0045, Japan.
authors: Teruhiko
authors: T
authors: Yoshida
authors: Genomics and Epigenomics of Cancer Prediction Program, Institute of Predictive and Personalized Medicine of Cancer (IMPPC), 08916 Badalona, Spain.
authors: Jun
authors: J
authors: Yokota
authors: Center for Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
authors: Fumihiko
authors: F
authors: Matsuda
authors: Division of Division of Molecular Medicine, Aichi Cancer Center Research Institute, Chikusa-ku, Nagoya 464-8681, Japan.
authors: Keitaro
authors: K
authors: Matsuo
authors: Center for Antibody and Vaccine Therapy, Research Hospital, Institute of Medical Science, The University of Tokyo, Tokyo 108-0071, Japan.|Department of Medical Oncology and Cancer Center, Shiga University of Medical Science, Otsu 520-2121, Japan.
authors: Yataro
authors: Y
authors: Daigo
authors: Laboratory for Genotyping Development, Center for Integrative Medical Sciences, RIKEN, Yokohama 113-8510, Japan.
authors: Michiaki
authors: M
authors: Kubo
authors: Division of Genome Biology, National Cancer Center Research Institute, Tokyo 104-0045, Japan.
authors: Takashi
authors: T
authors: Kohno
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics*; D000077192:Adenocarcinoma of Lung; D066246:ErbB Receptors / Q000235:genetics*; D051858:Forkhead Transcription Factors / Q000235:genetics; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D000949:Histocompatibility Antigens Class II / Q000235:genetics*; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D015203:Reproducibility of Results; D012307:Risk Factors
chemical_list: C576732:FOXP4 protein, human; D051858:Forkhead Transcription Factors; D000949:Histocompatibility Antigens Class II; D066246:ErbB Receptors