DNA damage response (DDR) variants and effects on the tumor transcriptome and microenvironment in east Asian (EA) prostate cancers (PCa).

Abstract

75 Background: Aberrations of the DDR pathway have been shown to be prognostic of survival and predictive of PARP inhibition in PCa. We have previously reported on the prevalence of germline DDR mutations based on a 32-gene set in localized PCa in EA men, and observed comparable rates with that of White men. Here, we performed additional analyses investigating for associations between DDR variants to the somatic transcriptome of localized PCa. Methods: We utilized a prospectively recruited cohort of 172 EA patients, with centrally assessed Gleason’s score (GS) by an expert pathologist. Germline profiling was performed by whole exome sequencing (100X) using the Illumina Novaseq (CA). Joint genotyping was performed to annotate variants that were deemed to be pathogenic (P)/likely pathogenic (LP)/conflict of interest pathogenic (CIP) based on the CADD and REVEL scores. Tumor transcriptome was profiled using the Decipher Genomic Classifier (GC, Veracyte, CA) based on the Affymetrix ST array (ThermoFisher, CA). Results: Among the subset of 172 EA men, we observed DDR variants in 26 (15%) patients, which was comparable to the larger cohort of 890 men from the same institution. Among the DDR mutations, 2 (7.7%) were classified as P/LP, while 24 (92.3%) were CIP. Decipher GC scores were comparable between patients with and without DDR mutations (median GC score 0.87 vs 0.53, Mann-Whitney U P=0.10). For luminal-basal subtyping by either the PAM50 and Prostate specific subtyping models, we did not observe a difference for the basal (P=0.48) and luminal subtypes (P=0.21). Interestingly, DNA repair gene-set expression were comparable between patients with DDR mutations versus those without (median score -0.2 vs -0.17). However, we observed microenvironment differences for immune-related genes, where patients harboring DDR mutations manifested a less immune-suppressive environment versus those without (PDL2: -0.15 vs 0.2; Treg: 0.09 vs 0.13; MDSC: 0.03 vs 0.07, respectively). Conclusions: Herein, we report an extension of our previous work (Lua, et al. ASCO GU, 2023), where we show potential linkages between the germline DDR variant status and the tumor transcriptome. Our findings suggest the influence of germline DDR variants that extends beyond tumorigenesis.