BOT-3 GENOME-WIDE ASSOCIATION STUDY OF INTRACRANIAL GERM CELL TUMORS: A COMMON DELETION AT BAK1 ATTENUATES THE ENHANCER ACTIVITY AND CONFERS RISK FOR THE BRAIN TUMORS IN CHILDREN ADOLESCENTS AND YOUNG ADULTS

Intracranial germ cell tumors (IGCTs) are rare brain tumors that mainly occur in children, adolescents and young adults with a particularly high incidence in East Asian populations. The biological basis of these tumors is still largely unknown. We conduct a genome-wide association study (GWAS) of 133 patients with IGCTs and 762 controls of Japanese ancestry by using Infinium Asian Screening Array and other molecular biology methods. 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. Expression quantitative trait locus (eQTL) analysis using the GTEx dataset reveals that the risk allele of rs3831846 has a down-regulating effect on BAK1 expression in a wide range of tissues. Further in-vitro reporter assays reveal rs3831846 to be a functional variant attenuating the enhancer activity. BAK1 is a pro-apoptotic member of the BCL-2 family, thus our results suggested that the risk allele may contribute to IGCTs predisposition through down-regulating 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). Of the 57 loci, 11 exhibit significant association with IGCTs and these loci were implicated in a broad range of biological pathways, including KIT/KITLG signaling, apoptosis regulation, and telomerase activity. The risk allele frequency of rs3831846 is higher in east Asia than Europe (0.49 vs. 0.20), which may provide a partial explanation for the ethnic difference in incidence. Nevertheless, our results suggest the shared genetic susceptibility of GCTs beyond ethnicity and primary sites.