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.
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.
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).
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.
Journal of the National Cancer Institute. 2026 Mar 30 [Epub ahead of print]
Shannon M Sullivan, John Lane, Abigail Standafer, James Mcfeeters, Aubrey K Hubbard, Erica K Langer, Anthony J Hooten, Michelle A Roesler, Joanna J Gell, Mark Krailo, A Lindsay Frazier, James F Amatruda, Nathan Pankratz, Jenny N Poynter
Department of Laboratory Medicine and Pathology, Division of Molecular Pathology and Genomics, University of Minnesota, Minneapolis, MN, USA., Department of Laboratory Medicine and Pathology, Division of Computational Biology, University of Minnesota, Minneapolis, MN, USA., Department of Pediatrics, Division of Epidemiology and Clinical Research, University of Minnesota, Minneapolis, MN, USA., Center for Cancer and Blood Disorders, Connecticut Children's Medical Center, Hartford, CT, USA., Keck School of Medicine, University of Southern California, Los Angeles, CA, USA., Dana Farber Cancer Institute, Boston, MA, USA., Cancer and Blood Disease Institute, Division of Hematology-Oncology, Children's Hospital of Los Angeles, Los Angeles, CA, USA.