The distinct molecular profile of metastatic prostate cancer in the mixed Brazilian population.

The carcinogenesis of metastatic prostate cancer results from complex interactions between genetic and environmental factors. The genomic profiles of admixed populations, such as Brazilians, are still poorly explored, offering an opportunity to better understand the contribution of germline and somatic variants in these patients. In this multicenter study, 193 men with metastatic prostate cancer, who underwent matched tumor-normal exome sequencing, were enrolled from all five Brazilian macro-regions. Pathogenic and likely pathogenic germline variants in well-known prostate cancer genes were identified in only 5.7% of the patients, with one case (0.5%) harboring the TP53 p.(Arg337His) Brazilian founder variant. Variants in WNT9B, recently associated with familial prostate cancer, were identified in an additional 2.1% of the patients. In contrast to the germline data, somatic results were obtained in only a subset of patients. Regarding homologous recombination deficiency, 21.8% of patients harbored tumor loss-of-function variants in ATM, CDK12, BRCA2, and FANCA. Even with the low success rate of tumor samples, our data demonstrated that most loss-of-function variants in homologous recombination pathway genes occur as somatic events. Our findings also highlight the distinct germline genomic profile of the Brazilian population and underscore the challenges associated with performing comprehensive analyses on formalin-fixed paraffin-embedded samples.