Uncovering novel germline variants associated with testicular germ cell tumors by exome sequencing
Por:
Cuevas-Estrada, B, Ríos-Rodríguez, JA, García-Pacheco, JA, Wegman-Ostrosky, T, Cervera, A, Alcaraz, N, Montalvo-Casimiro, M, Barrón-Hernández, A, Castro-Hernández, C, Jiménez-Ríos, MA, Sobrevilla-Moreno, N, Arriaga-Canon, C, Herrera, L, González-Barrios, R
Publicada:
1 jun 2026
Resumen:
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.
Filiaciones:
Cuevas-Estrada, B:
Inst Nacl Cancerol, Lab Patol Mol & Inmunopatol, Mexico City 14080, DF, Mexico
Ríos-Rodríguez, JA:
Inst Nacl Cancerol, Lab Patol Mol & Inmunopatol, Mexico City 14080, DF, Mexico
Tecnol Monterrey, Escuela Med & Ciencias Salud, Mexico City 14380, Mexico
García-Pacheco, JA:
Inst Nacl Cancerol, Lab Patol Mol & Inmunopatol, Mexico City 14080, DF, Mexico
Wegman-Ostrosky, T:
Inst Nacl Cancerol, Precis Med Lab, Subdirect Res Unit, Mexico City 14080, Mexico
Cervera, A:
Inst Nacl Med Genom INMEGEN, Lab Genom Biomed & Bioinformat, Mexico City 14610, Mexico
Alcaraz, N:
Danish Canc Soc, Danish Canc Inst, Ctr Epigenet Cell Memory, DK-2100 Copenhagen, Denmark
Univ Copenhagen, Novo Nord Fdn Ctr Prot Res, Dept Cellular & Mol Med, DK-2200 Copenhagen, Denmark
Montalvo-Casimiro, M:
Inst Nacl Cancerol, Lab Patol Mol & Inmunopatol, Mexico City 14080, DF, Mexico
Barrón-Hernández, A:
Inst Nacl Cancerol, Lab Patol Mol & Inmunopatol, Mexico City 14080, DF, Mexico
Castro-Hernández, C:
Univ Nacl Autonoma Mexico, Inst Invest Biomed, Mexico City 14080, Mexico
Jiménez-Ríos, MA:
Inst Nacl Cancerol, Dept Urol, Mexico City 14080, Mexico
Sobrevilla-Moreno, N:
Inst Nacl Cancerol, Dept Oncol Med, Mexico City 14080, Mexico
Arriaga-Canon, C:
Tecnol Monterrey, Escuela Med & Ciencias Salud, Mexico City 14380, Mexico
Inst Nacl Med Genomica INMEGEN, Lab Innovac & Med Precis, Nucleo A, Mexico City 14610, Mexico
Herrera, L:
Tecnol Monterrey, Escuela Med & Ciencias Salud, Mexico City 14380, Mexico
Inst Nacl Ciencias Med & Nutr Salvador Zubiran, Direcc Invest, Mexico City 14080, Mexico
González-Barrios, R:
Inst Nacl Cancerol, Lab Patol Mol & Inmunopatol, Mexico City 14080, DF, Mexico
Univ Nacl Autonoma Mexico, Fac Ciencias, Dept Biol Celular, Mexico City 04510, Mexico
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