Genome-wide association study identifies gastric cancer susceptibility loci at 12q24.11-12 and 20q11.21

Chizu Tanikawa; Yoichiro Kamatani; Osamu Toyoshima; Hiromi Sakamoto; Hidemi Ito; Atsushi Takahashi; Yukihide Momozawa; Makoto Hirata; Nobuo Fuse; Takako Takai-Igarashi; Atsushi Shimizu; Makoto Sasaki; Taiki Yamaji; Norie Sawada; Motoki Iwasaki; Shoichiro Tsugane; Mariko Naito; Asahi Hishida; Kenji Wakai; Norihiro Furusyo; Yoshinori Murakami; Yusuke Nakamura; Issei Imoto; Johji Inazawa; Isao Oze; Naomi Sato; Fumihiko Tanioka; Haruhiko Sugimura; Hiroshi Hirose; Teruhiko Yoshida; Keitaro Matsuo; Michiaki Kubo; Koichi Matsuda

doi:10.1111/cas.13815

Genome-wide association study identifies gastric cancer susceptibility loci at 12q24.11-12 and 20q11.21

Cancer Sci. 2018 Dec;109(12):4015-4024. doi: 10.1111/cas.13815. Epub 2018 Oct 31.

Authors

Chizu Tanikawa¹, Yoichiro Kamatani², Osamu Toyoshima³, Hiromi Sakamoto⁴, Hidemi Ito⁵, Atsushi Takahashi^{2

6}, Yukihide Momozawa⁷, Makoto Hirata¹, Nobuo Fuse⁸, Takako Takai-Igarashi⁸, Atsushi Shimizu⁹, Makoto Sasaki⁹, Taiki Yamaji¹⁰, Norie Sawada¹⁰, Motoki Iwasaki¹⁰, Shoichiro Tsugane¹¹, Mariko Naito^{12

13}, Asahi Hishida¹², Kenji Wakai¹², Norihiro Furusyo¹⁴, Yoshinori Murakami¹⁵, Yusuke Nakamura¹⁶, Issei Imoto^{17

18}, Johji Inazawa¹⁹, Isao Oze⁵, Naomi Sato²⁰, Fumihiko Tanioka^{21

22}, Haruhiko Sugimura²¹, Hiroshi Hirose²³, Teruhiko Yoshida⁴, Keitaro Matsuo⁵, Michiaki Kubo⁷, Koichi Matsuda^{1

24}

Affiliations

¹ Laboratory of Genome Technology, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
² Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan.
³ Gastroenterology, Toyoshima Endoscopy Clinic, Tokyo, Japan.
⁴ Division of Genetics, National Cancer Center Research Institute, Tokyo, Japan.
⁵ Division of Molecular and Clinical Epidemiology, Aichi Cancer Center Research Institute, Aichi, Japan.
⁶ Department of Genomic Medicine, Research Institute, National Cerebral and Cardiovascular Center, Osaka, Japan.
⁷ Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan.
⁸ Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan.
⁹ Iwate Tohoku Medical Megabank Organization, Iwate Medical University, Iwate, Japan.
¹⁰ Division of Epidemiology, Center for Public Health Sciences, National Cancer Center, Tokyo, Japan.
¹¹ Center for Public Health Sciences, National Cancer Center, Tokyo, Japan.
¹² Department of Preventive Medicine, Nagoya University Graduate School of Medicine, Aichi, Japan.
¹³ Department of Oral Epidemiology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
¹⁴ Department of Environmental Medicine and Infectious Disease, Kyushu University, Fukuoka, Japan.
¹⁵ Division of Molecular Pathology, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
¹⁶ Departments of Medicine and Surgery and Center for Personalized Therapeutics, The University of Chicago, Chicago, USA.
¹⁷ Department of Human Genetics, Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan.
¹⁸ Division of Molecular Genetics, Aichi Cancer Center Research Institute, Aichi, Japan.
¹⁹ Department of Molecular Cytogenetics, Medical Research Institute and Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
²⁰ Department of Clinical Nursing, Hamamatsu University School of Medicine, Shizuoka, Japan.
²¹ Department of Tumor Pathology, Hamamatsu University School of Medicine, Shizuoka, Japan.
²² Division of Pathology, Iwata City Hospital, Shizuoka, Japan.
²³ Health Center, Keio University, Tokyo, Japan.
²⁴ Laboratory of Clinical Genome Sequencing, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, University of Tokyo, Tokyo, Japan.

Abstract

Gastric cancer is the third leading cause of cancer mortality in Japan and worldwide. Although previous studies identify various genetic variations associated with gastric cancer, host genetic factors are largely unidentified. To identify novel gastric cancer loci in the Japanese population, herein, we carried out a large-scale genome-wide association study using 6171 cases and 27 178 controls followed by three replication analyses. Analysis using a total of 11 507 cases and 38 904 controls identified two novel loci on 12q24.11-12 (rs6490061, P = 3.20 × 10^-8 with an odds ratio [OR] of 0.905) and 20q11.21 (rs2376549, P = 8.11 × 10^-10 with an OR of 1.109). rs6490061 is located at intron 19 of the CUX2 gene, and its expression was suppressed by Helicobacter pylori infection. rs2376549 is included within the gene cluster of DEFB families that encode antibacterial peptides. We also found a significant association of rs7849280 in the ABO gene locus on 9q34.2 (P = 2.64 × 10^-13 with an OR of 1.148). CUX2 and ABO expression in gastric mucosal tissues was significantly associated with rs6490061 and rs7849280 (P = 0.0153 and 8.00 × 10^-11 ), respectively. Our findings show the crucial roles of genetic variations in the pathogenesis of gastric cancer.

Keywords: ABO; DEFB; CUX2; gastric cancer; genome-wide association study.

MeSH terms

ABO Blood-Group System / genetics
Adult
Aged
Aged, 80 and over
Case-Control Studies
Chromosomes, Human, Pair 12 / genetics*
Chromosomes, Human, Pair 20 / genetics*
Chromosomes, Human, Pair 9 / genetics
Female
Gene Expression Regulation
Genetic Predisposition to Disease
Genome-Wide Association Study / methods*
Helicobacter Infections / genetics
Homeodomain Proteins / genetics
Humans
Japan
Male
Middle Aged
Polymorphism, Single Nucleotide*
Stomach Neoplasms / genetics*
Stomach Neoplasms / microbiology
Young Adult
beta-Defensins / genetics

Substances

ABO Blood-Group System
Homeodomain Proteins
beta-Defensins

Abstract

MeSH terms

Substances

Grants and funding