Despite having a favorable response to platinum-based chemotherapies, ~15% of Testicular Germ-Cell Tumor (TGCT) patients are platinum-resistant. Mortality rates among Latin American countries have remained constant over time, which makes the study of this population of particular interest. To gain insight into this phenomenon, we conducted whole-exome sequencing, microarray-based comparative genomic hybridization, and copy number analysis of 32 tumors from a Mexican cohort, of which 18 were platinum-sensitive and 14 were platinum-resistant. We incorporated analyses of mutational burden, driver mutations, and SNV and CNV signatures. DNA breakpoints in genes were also investigated and might represent an interesting research opportunity. We observed that sensitivity to chemotherapy does not seem to be explained by any of the mutations detected. Instead, we uncovered CNVs, particularly amplifications on segment 2q11.1 as a novel variant with chemosensitivity biomarker potential. Our data shed light into understanding platinum resistance in a Latin-origin population.

Testicular germ-cell tumors (TGCT) have been widely recognized for their outstanding survival rates, commonly attributed to their high sensitivity to cisplatin-based therapies. Despite this, a subset of patients develops cisplatin resistance, for whom additional therapeutic options are unsuccessful, and ~20% of them will die from disease progression at an early age. Several efforts have been made trying to find the molecular bases of cisplatin resistance. However, this phenomenon is still not fully understood, which has limited the development of efficient biomarkers and precision medicine approaches as an alternative that could improve the clinical outcomes of these patients. With the aim of providing an integrative landscape, we review the most recent genomic and epigenomic features attributed to chemoresponse in TGCT patients, highlighting how we can seek to combat cisplatin resistance through the same mechanisms by which TGCTs are particularly hypersensitive to therapy. In this regard, we explore ongoing treatment directions for resistant TGCT and novel targets to guide future clinical trials. Through our exploration of recent findings, we conclude that epidrugs are promising treatments that could help to restore cisplatin sensitivity in resistant tumors, shedding light on potential avenues for better prognosis for the benefit of the patients.

Despite having a favorable response to platinum-based chemotherapies, ∼15% of Testicular Germ Cell Tumor (TGCT) patients are platinum resistant. Mortality rates among Latin American countries have remained constant over time, which makes the study of this population of particular interest. To gain insight into this phenomenon, we conducted whole-exome sequencing, microarray-based comparative genomic hybridization, and copy number analysis of 32 tumors from a Mexican cohort, of which 18 were platinum sensitive and 14 were platinum resistant. We incorporated analyses of mutational burden, driver mutations, SNV and CNV signatures. We observed that sensitivity to chemotherapy does not seem to be explained by any of the mutations detected. Instead, we uncovered CNVs, particularly amplification of 2q11.1 as a novel variant with chemosensitivity biomarker potential. DNA breakpoints in genes were also investigated and might represent an interesting research opportunity. Our data sheds light into understanding platinum resistance in a poorly characterized population.

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.