Testicular germ cell tumors (TGCT) are highly heritable malignancies that display increasing incidence worldwide, with rising mortality rates particularly evident among Hispanic men. However, genomic studies of TGCT have largely focused on European cohorts, limiting accurate risk prediction in other populations. We investigated rare germline variants contributing to TGCT susceptibility in a Hispanic cohort. Exome sequencing data (mean depth 60x) from 40 Mexican TGCT patients were analyzed against two ancestry-matched control groups using gene-based aggregation analyses and single-variant association. Top candidate variants were validated and replicated in an independent cohort of 211 TGCT patients, with Mexican individuals from the PAGE study serving as a third control group. Gene-based testing revealed seven genes, including MAP3K5, VAV2, and CAPN8, with nominal associations. Three previously unreported variants: rs2273499 in ARFGAP1 (OR 3.72), rs147153778 in SLCO4A1 (OR 2.21), and rs79783591 in MC4R (OR 2.31), showed statistically significant results and consistent directionality in the replication cohort, representing suggestive TGCT risk variants that warrant further validation, although none reached exome-wide significance. All three also displayed preliminary associations with mortality, indicating potential prognostic relevance. These findings provide exploratory, population-enriched signals of genetic susceptibility to TGCT in Hispanics. Altogether, they emphasize the critical need for more inclusive genomic research in underrepresented populations and provide a foundation for future investigations aimed at improving population-tailored risk assessment and prognostic tools.
NAR cancer. 2026 Apr 20*** epublish ***
Berenice Cuevas-Estrada, Juan A Ríos-Rodríguez, José A García-Pacheco, Talia Wegman-Ostrosky, Alejandra Cervera, Nicolas Alcaraz, Michel Montalvo-Casimiro, Alejandra Barrón-Hernández, Clementina Castro-Hernández, Miguel A Jiménez-Ríos, Nora Sobrevilla-Moreno, Cristian Arriaga-Canon, Luis A Herrera, Rodrigo González-Barrios
Laboratorio de Regulación de la Cromatina y Genómica, Instituto Nacional de Cancerología,Mexico City 14080,Mexico., Precision Medicine Laboratory, Sub-Direction of Research Unit, Instituto Nacional de Cancerología, Mexico City 14080,Mexico., Laboratorio de Genómica Biomédica y Bioinformática, Instituto Nacional de Medicina Genómica (INMEGEN),Mexico City 14610,Mexico., Center for Epigenetic Cell Memory, Danish Cancer Institute, Danish Cancer Society,Copenhagen 2100,Denmark., Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México (UNAM),Mexico City 14080,Mexico., Departamento de Urología, Instituto Nacional de Cancerología,Mexico City 14080,Mexico., Departamento de Oncología Médica, Instituto Nacional de Cancerología,Mexico City 14080,Mexico., Laboratorio de Innovación y Medicina de Precisión, Núcleo A, Instituto Nacional de Medicina Genómica (INMEGEN),Mexico City 14610,Mexico., Escuela de Medicina y Ciencias de la Salud, Tecnológico de Monterrey,Ciudad de México 14380,México.