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PubMed · 41941753

Overlapping genetic etiology of pediatric and adult germ cell tumors.

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
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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.

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HumansNeoplasms, Germ Cell and EmbryonalMaleGenome-Wide Association StudyTesticular NeoplasmsFemaleChildAdolescentInfantChild, PreschoolGenetic Predisposition to DiseasePolymorphism, Single NucleotideYoung AdultOvarian NeoplasmsTranscription FactorsNerve Tissue ProteinsBrain NeoplasmsAdultIntracellular Signaling Peptides and Proteinsbcl-2 Homologous Antagonist-Killer ProteinInfant, NewbornCase-Control StudiesJournal Article

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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. 2026-09-01. Overlapping genetic etiology of pediatric and adult germ cell tumors.. https://doi.org/10.1093/jnci%2Fdjag097

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