[BO] Oral Presentation Award Session

[BO-2] A common deletion at BAK1 attenuates enhancer activity and confers risk of intracranial germ cell tumors

^○Kyuto Sonehara¹, Yui Kimura^2,3, Yoshiko Nakano^3,4, Tatsuya Ozawa³, Meiko Takahashi⁵, Ken Suzuki¹, Takashi Fujii^6,7,8, Yuko Matsushita^7,8, Arata Tomiyama^6,7,8, Toshihiro Kishikawa^1,9, Kenichi Yamamoto¹, Tatsuhiko Naito^1,10, Tomonari Suzuki¹¹, Shigeru Yamaguchi¹², Tomoru Miwa¹³, Hikaru Sasaki¹³, Masashi Kitagawa¹⁴, Naoyuki Ohe¹⁵, Junya Fukai¹⁶, Hideki Ogiwara², Atsufumi Kawamura¹⁷, Satoru Miyawaki¹⁸, Fumihiko Matsuda⁵, Nobutaka Kiyokawa², Koichi Ichimura^3,8, Ryo Nishikawa¹¹, Yukinori Okada^1,10,19,20, Keita Terashima² (1.Osaka University Graduate School of Medicine, Suita, Japan, 2.National Center for Child Health and Development, Tokyo, Japan, 3.National Cancer Center Research Institute, Tokyo, Japan, 4.The University of Tokyo Hospital, Tokyo, Japan, 5.Kyoto University Graduate School of Medicine, Kyoto, Japan, 6.National Defense Medical College, Tokorozawa, Japan, 7.Juntendo University School of Medicine, Tokyo, Japan, 8.Graduate School of Medicine, Juntendo University, Tokyo, Japan, 9.Aichi Cancer Center Hospital, Nagoya, Japan, 10.Graduate School of Medicine, the University of Tokyo, Tokyo, Japan, 11.Saitama Medical University International Medical Center, Hidaka, Japan, 12.Faculty of Medicine, Hokkaido University, Sapporo, Japan, 13.Keio University School of Medicine, Tokyo, Japan, 14.Shizuoka Children's Hospital, Shizuoka, Japan, 15.Graduate School of Medicine, Gifu University, Gifu, Japan, 16.Wakayama Medical University School of Medicine, Kimiidera, Japan, 17.Hyogo Prefectural Kobe Children’s Hospital, Kobe, Japan, 18.Faculty of Medicine, the University of Tokyo, Tokyo, Japan, 19.Immunology Frontier Research Center (WPI-IFReC), Osaka University, Suita, Japan, 20.RIKEN Center for Integrative Medical Sciences, Yokohama, Japan)

Intracranial germ cell tumors (IGCTs) are rare brain tumors mainly diagnosed in children and adolescents, with a strikingly higher incidence in East Asian countries than in Western ones (e.g. an incidence of 2.7/million/year in Japan but 0.6/million/year in the United States). Due to the low disease incidence, only a limited amount of basic research has been conducted on this rare disease. Here, we perform an initial genome-wide association study (GWAS) of 133 IGCTs cases and 762 controls. The case sample size is the largest ever reported on IGCTs genetics, enabling us to identify a significant locus at 6p21 (P=2.4×10^-9, odds ratio 2.46), which is replicated in an independent dataset of 99 cases and 1026 controls (P=1.7×10^-7). The lead variant rs3831846 (risk allele frequency=0.43) is a 4-bp deletion polymorphism residing in an enhancer adjacent to BAK1. Expression quantitative trait loci (eQTL) analysis reveals that the risk allele has a widespread down-regulating effect on BAK1. Moreover, in-vitro reporter assays validate that the risk allele reduces the enhancer activity. Finally, given the histological resemblance between IGCTs and testicular GCTs (TGCTs), a subtype of the more common gonadal GCTs, we examine the statistics in our IGCTs GWAS for 57 TGCTs risk loci from the European GWAS. The effect sizes show a positive overall correlation between Japanese IGCTs and European TGCTs (P=1.3×10^-4, Spearman’s ρ=0.48), with 11 loci significantly associated with IGCTs (P＜0.05). Our study indicates the shared genetic background of GCTs beyond ethnicity and primary sites.