Overlapping genetic etiology of pediatric and adult germ cell tumors

Abstract Background Germ cell tumors (GCTs) are heterogeneous neoplasms arising from primordial germ cells. While genome-wide association studies (GWAS) have identified numerous susceptibility loci for adult testicular GCTs (TGCTs), the heritable basis of pediatric TGCT and GCTs that arise outside the testes remain poorly understood. Methods We conducted a multi-ancestry GWAS of pediatric GCTs, including 1,927 cases from the Germ Cell Tumor Epidemiology Study (GaMETES) and 10,601 controls. Cases were diagnosed with testicular (n = 678), ovarian (n = 441), intracranial (n = 435), and extragonadal (n = 373) GCT between the ages of 0 to 19 years. Results We identified four loci reaching genome-wide significance, including variants near BAK1 (chr 6: rs3831846), SPRY4 (chr 5: rs12515244), DMRT1 (chr 9: rs10815910), and DEPTOR (chr 8: rs13277786). Additional genome-wide significant associations were identified in subgroup analyses, including six loci for intracranial GCTs (rs2758612 PMF1/BGLAP, rs9854760 PLCL2, rs6851498 KIT, rs11816992 on chromosome 10, rs3830273 TFAM, and rs13054014 LZTR1), one locus for testicular GCT (rs1907702 KITLG), and one locus for males (rs4610628 MAD1L1). After Bonferroni correction, 18 of 78 previously reported TGCT loci were significantly associated with GCT overall or in at least one subgroup with a particularly strong correlation between TGCT and iGCT effect estimates (rho = 0.63, P = 5.5x10−10). Expression quantitative trait locus (eQTL) analyses identified candidate genes in the regions identified on chromosome 6 (BAK1, LINC003366, and ITPR3) and chromosome 8 (DEPTOR and RP11-760H22.2). Conclusions Our data support a role for germline genetic variation in the development of GCT in locations outside the testes and highlight shared genetic architecture across age group and tumor location.