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 Ogiwara, Atsufumi Kawamura, Satoru Miyawaki, Fumihiko Matsuda, Nobutaka Kiyokawa, Koichi Ichimura, Ryo Nishikawa, Yukinori Okada () and Keita Terashima ()
Additional contact information
Kyuto Sonehara: Osaka University Graduate School of Medicine
Yui Kimura: National Center for Child Health and Development
Yoshiko Nakano: National Cancer Center Research Institute
Tatsuya Ozawa: National Cancer Center Research Institute
Meiko Takahashi: Kyoto University Graduate School of Medicine
Ken Suzuki: Osaka University Graduate School of Medicine
Takashi Fujii: National Defense Medical College
Yuko Matsushita: Juntendo University School of Medicine
Arata Tomiyama: National Defense Medical College
Toshihiro Kishikawa: Osaka University Graduate School of Medicine
Kenichi Yamamoto: Osaka University Graduate School of Medicine
Tatsuhiko Naito: Osaka University Graduate School of Medicine
Tomonari Suzuki: Saitama Medical University International Medical Center
Shigeru Yamaguchi: Hokkaido University
Tomoru Miwa: Keio University School of Medicine
Hikaru Sasaki: Keio University School of Medicine
Masashi Kitagawa: Shizuoka Children’s Hospital
Naoyuki Ohe: Gifu University
Junya Fukai: Wakayama Medical University School of Medicine
Hideki Ogiwara: National Center for Child Health and Development
Atsufumi Kawamura: Hyogo Prefectural Kobe Children’s Hospital
Satoru Miyawaki: the University of Tokyo
Fumihiko Matsuda: Kyoto University Graduate School of Medicine
Nobutaka Kiyokawa: National Center for Child Health and Development
Koichi Ichimura: National Cancer Center Research Institute
Ryo Nishikawa: Saitama Medical University International Medical Center
Yukinori Okada: Osaka University Graduate School of Medicine
Keita Terashima: National Center for Child Health and Development

Nature Communications, 2022, vol. 13, issue 1, 1-9

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-32005-9

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