Germline correlates of clinical outcomes in aggressive prostate cancer subtypes treated with radiation therapy.
Authors: Cerrato Grace , Sanjeev Rishab , Pompa Isabella R , Kozono David E. , DAmico Anthony Victor , Nguyen Paul L. , Miyamoto David T , Efstathiou Jason A. , Kamran Sophia C. 
Published: February 2025

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Background:
Research on the genetic profile of cribriform pattern (CP) and intraductal carcinoma (IDC) subtypes of aggressive prostate cancer (PCa) is limited. We evaluated germline mutations in CP/IDC PCa patients receiving radiation therapy (RT) to assess the role of familial high-risk (FHR) and DNA damage repair (DDR) mutations associated with these pathologies and clinical outcomes.
Methods:
This multi-institutional study included CP/IDC PCa patients treated with RT who consented to germline whole exome sequencing (WES). WES data was annotated using Ensembl Variant Predictor, ClinVar, and OncoKB to identify pathogenic/oncogenic mutations. Mutational frequencies were calculated in R. Clinical data and disease progression (biochemical recurrence [BCR], local relapse [LR], distant metastases [DM]) were assessed. Gene and clinical outcome associations were evaluated using the Kaplan-Meier method and log-rank test (p < 0.05 for significance, Benjamini-Hochberg FDR of 0.1 used for multiple hypothesis testing).
Results:
Of 1,392 CP/IDC patients treated with RT between 2010-2024, 80 had germline sequencing, and 49 had WES data (12 CP, 24 IDC, 13 CP+IDC); 45 were localized at diagnosis (28 high-, 16 intermediate-, 1 low-risk). Median age at diagnosis was 64 years. 39 (80%) received RT post-radical prostatectomy (RP, salvage) and 10 (20%) for intact prostate (definitive). Median follow-up (FU, months) was 64.5 after diagnosis and 60.3 after RT. At last FU post-RT, 14 (29%) exhibited BCR, 12 (24%) had LR, and 9 (18%) had DM, with progression rates of 83% in CP and IDC, and 77% in CP+IDC. Five-year OS from diagnosis was 94.8% (95% CI, 80.4-98.7), and BCR-free survival (defined as no BCR post-salvage or post-definitive RT) was 69% (95% CI, 47.8-83). Of the 98 FHR and 280 DDR genes analyzed, 4 (8%) and 20 (40%) patients had confirmed mutations, respectively. Of the 24 patients with germline mutations, 20 (83%) had IDC pathology. DDR mutations associated with improved BCR-free survival, HR 0.14, 95%CI 0.03-0.70, p=0.007. Notably, 19 patients had a pathogenic MSH3 deletion, which was associated with improved BCR-free survival, HR 0.17, 95%CI 0.03-0.83, p=0.02. Additionally, 20 patients had pathogenic stop-gains/deletions, 17 (85%) of whom had IDC pathology. Five oncogene mutations were identified in DDR genes ATR, TP53 and ATM, and tumor suppressor genes SHDA and DPYS previously implicated in PCa, all in IDC samples.
Conclusions:
Pathogenic germline mutations, particularly DDR variants, are significantly associated with aggressive IDC pathology. Continued evaluation in non-CP/IDC patients undergoing RT is needed to examine associations between mutations, subtypes, and outcomes. Mutations in DDR genes, such as MSH3 deletion, were linked to improved BCR-free survival, highlighting the potential role of DDR alterations in therapeutic response of RT patients with aggressive PCa subtypes.