High-Grade Early-Onset Prostate Cancer: Assessment of TMPRSS2::ERG-Negative Tumors Suggests Low Frequency of Germline Alterations and a Pathogenic Role for HOXB13

Early onset prostate cancer (EOPC; defined herein as prostate cancer [PCa] affecting men ≤ 55 years-old) tends to show low histologic grade, likely representing early detection of indolent tumors that would otherwise be diagnosed later in life. A small subset of EOPC exhibits Gleason scores consistent with high-risk disease (Grade Groups 4 to 5; high-grade EOPC [HG-EOPC] hereafter). In this study, we assess the clinicopathologic features of HG-EOPC, with genomic analysis of ERG-negative cases. We assessed HG-EOPC using immunohistochemistry for ERG (as a surrogate marker of TMPRSS2::ERG), PMS2 (as a surrogate marker of MLH1/PMS2 inactivation), and MSH6 (as a surrogate marker of MSH2/MSH6 inactivation). Selected ERG negative cases were assessed using Oncopanel, which interrogates 447 genes, including PCa-relevant genes. Ninety-six samples from 96 individual patients (median age: 52 y; range: 40 to 55 y) were included in the study. Immunohistochemical staining with ERG was performed in 95 cases, 52 (54%) of which showed negative staining. PMS2 was performed in 93 cases, being retained in 92 (98.9%) and lost in 1 (1.1%). MSH6 was performed in 96 cases, being retained in 92 (95.8%), lost in 2 (2.1%), and equivocal in 2 (2.1%). Sequencing of 23 ERG-negative primary tumors showed enrichment for alterations that are typically associated with castration resistance, including loss of 8p (>50%), gains of 8q (>50%), and inactivation of CDK12 (n=4). The cohort also showed a relatively high frequency of pathogenic TP53 (n=7) and SPOP (n=4) variants. Pathogenic BRCA2 variants and mismatch repair deficiency were identified in 1 case each. Interestingly, >50% of the tumors showed HOXB13 amplification. In conclusion, TMPRSS2::ERG fusion-negative HG-EOPC shows a high frequency of genomic alterations typically enriched in castration-resistant neoplasms but variants of potential germline origin (including those in mismatch repair genes) are rare. These results demonstrate that HG-EOPC is driven largely by somatic events.