Germline DNA Repair and Immune-metabolic Alterations Suggest a Potentially Distinct Form of Early-onset Prostate...

Early-onset prostate cancer (PCa) is more frequent in men of African descent; yet, the biological mechanisms underlying susceptibility remain unclear. While most germline studies have focused on DNA repair genes (DRGs), alternative pathways may also contribute to tumor initiation, which we aim to assess in this study.

We analyzed 71 Afro-Caribbean men diagnosed with early-onset PCa (≤51 yr old for sporadic cases and ≤56 yr old for familial cases). Germline testing combined targeted sequencing of 175 genes-including major DRGs-with whole-exome sequencing in patients without DRG alterations. Variants were filtered for rarity (minor allele frequency <0.01 in African populations) and their clinical classification as pathogenic or likely pathogenic (P/LP; ClinVar and ACMG/AMP guidelines). Genes were grouped by biological function.

Rare P/LP germline variants were identified in 37 patients (52.1%). Among these patients, ten carried a DRG variant (including one also harboring HOXB13 X285K), 26 carried at least one variant in immune-metabolic pathways (one also with HOXB13 X285K), and one carried only HOXB13 X285K. Recurrent truncating variants were found in FLG, PGAM2, and TYRP1. Although no statistically significant association was observed between molecular subgroups and clinical aggressiveness, DRG variants tended to occur in more high-risk tumors, whereas immune-metabolic alterations were more frequent in patients with low- or intermediate-risk disease.

This study reveals a broader germline landscape in early-onset PCa among men of African descent. Inherited immune-metabolic dysfunction may contribute to tumorigenesis through microenvironmental dysregulation, highlighting novel pathways for investigation in larger and ancestrally diverse cohorts.