Year: 2026
Type: article
Study design: Observational Study
Abstract: BACKGROUND: Germ cell tumors are heterogeneous neoplasms arising from primordial germ cells. Although genome-wide association studies have identified numerous susceptibility loci for adult testicular germ cell tumors, the heritable basis of pediatric testicular germ cell tumors and germ cell tumors that arise outside the testes remain poorly understood. METHODS: We conducted a multi-ancestry genome-wide association study of pediatric germ cell tumors, including 1927 cases from the Germ Cell Tumor Epidemiology Study and 10 601 controls. Cases were diagnosed with testicular (n = 678), ovarian (n = 441), intracranial (n = 435), and extragonadal (n = 373) germ cell tumor between the ages of 0 and 19 years. RESULTS: We identified 4 loci reaching genome-wide significance, including variants near BAK1 (chr 6: rs3831846), SPRY4 (chr 5: rs12515244), DMRT1 (chromosome [chr] 9: rs10815910), and DEPTOR (chr 8: rs13277786). Additional genome-wide statistically significant associations were identified in subgroup analyses, including 6 loci for intracranial germ cell tumors (rs2758612 [PMF1/BGLAP], rs9854760 [PLCL2], rs6851498 [KIT], rs11816992 on chromosome 10, rs3830273 [TFAM], and rs13054014 [LZTR1]), 1 locus for testicular germ cell tumor (rs1907702 [KITLG]), and 1 locus for males (rs4610628 [MAD1L1]). After Bonferroni correction, 18 of 78 previously reported testicular germ cell tumor loci were significantly associated with germ cell tumor overall or in at least 1 subgroup with a particularly strong correlation between testicular germ cell tumor and intracranial germ cell tumor effect estimates (rho = 0.63, P = 5.5 × 10-10). Expression quantitative trait locus (QTL) 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 germ cell tumors in locations outside the testes and highlight shared genetic architecture across age group and tumor location.
DOI: 10.1093/jnci/djag097
Institutions: University of Minnesota, Masonic Cancer Center, University of Connecticut, Connecticut Children's Medical Center, The Jackson Laboratory for Genomic Medicine, UConn Health, University of Southern California, Boston Children's Hospital, Dana-Farber Cancer Institute, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Children's Hospital Los Angeles
Language: English
Subfield: Surgery
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7150968612