講演情報

[BO-2]BAK1遺伝子近傍のcommon non-coding deletion多型はエンハンサー活性を減弱させ、頭蓋内胚細胞腫瘍の遺伝的リスクに寄与する

^○曽根原究人¹, 木村由依^2,3, 中野嘉子^3,4, 小澤達也³, 高橋めい子⁵, 鈴木顕¹, 藤井隆司^6,7,8, 松下裕子^7,8, 富山新太^6,7,8, 岸川敏博^1,9, 山本賢一¹, 内藤龍彦^1,10, 鈴木智成¹¹, 山口秀¹², 三輪点¹³, 佐々木光¹³, 北川雅史¹⁴, 大江直行¹⁵, 深井順也¹⁶, 荻原英樹², 河村淳史¹⁷, 宮脇哲¹⁸, 松田文彦⁵, 清河信敬², 市村幸一^3,8, 西川亮¹¹, 岡田随象^1,10,19,20, 寺島慶太² (1.大阪大学大学院医学系研究科, 2.国立成育医療研究センター, 3.国立がん研究センター, 4.東京大学医学部附属病院, 5.京都大学大学院医学研究科, 6.防衛医科大学校, 7.順天堂大学医学部, 8.順天堂大学大学院医学系研究科, 9.愛知県がんセンター, 10.東京大学大学院医学系研究科, 11.埼玉医科大学国際医療センター, 12.北海道大学医学部, 13.慶應義塾大学医学部, 14.静岡県立こども病院, 15.岐阜大学大学院医学系研究科, 16.和歌山県立医科大学医学部, 17.兵庫県立こども病院, 18.東京大学医学部, 19.大阪大学免疫学フロンティア研究センター, 20.理化学研究所生命医科学研究センター)

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.

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