A common deletion at BAK1 reduces enhancer activity and confers risk of intracranial germ cell tumors

Kyuto Sonehara, Yui Kimura, Yoshiko Nakano, Tatsuya Ozawa, Meiko Takahashi, Ken Suzuki, Takashi Fujii, Yuko Matsushita, Arata Tomiyama, Toshihiro Kishikawa, Kenichi Yamamoto, Tatsuhiko Naito, Tomonari Suzuki, Shigeru Yamaguchi, Tomoru Miwa, Hikaru Sasaki, Masashi Kitagawa, Naoyuki Ohe, Junya Fukai, Hideki OgiwaraAtsufumi Kawamura, Satoru Miyawaki, Fumihiko Matsuda, Nobutaka Kiyokawa, Koichi Ichimura, Ryo Nishikawa, Yukinori Okada, Keita Terashima

Research output: Contribution to journalArticlepeer-review

7 Citations (Scopus)


Intracranial germ cell tumors (IGCTs) are rare brain neoplasms that mainly occur in children and adolescents with a particularly high incidence in East Asian populations. Here, we conduct a genome-wide association study (GWAS) of 133 patients with IGCTs and 762 controls of Japanese ancestry. A common 4-bp deletion polymorphism in an enhancer adjacent to BAK1 is significantly associated with the disease risk (rs3831846; P = 2.4 × 10−9, odds ratio = 2.46 [95% CI: 1.83–3.31], minor allele frequency = 0.43). Rs3831846 is in strong linkage disequilibrium with a testicular GCTs susceptibility variant rs210138. In-vitro reporter assays reveal rs3831846 to be a functional variant attenuating the enhancer activity, suggesting its contribution to IGCTs predisposition through altering BAK1 expression. Risk alleles of testicular GCTs derived from the European GWAS show significant positive correlations in the effect sizes with the Japanese IGCTs GWAS (P = 1.3 × 10−4, Spearman’s ρ = 0.48). These results suggest the shared genetic susceptibility of GCTs beyond ethnicity and primary sites.

Original languageEnglish
Article number4478
JournalNature communications
Issue number1
Publication statusPublished - 2022 Dec

ASJC Scopus subject areas

  • General Physics and Astronomy
  • General Chemistry
  • General Biochemistry,Genetics and Molecular Biology


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