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Distinct profiles of DNA repair activity define favorable-risk prostate cancer subtypes with divergent outcome

Published:November 15, 2022DOI:https://doi.org/10.1016/j.clgc.2022.11.005

      Key take-home messages

      • This study first shows that high DNA repair activity is associated with high-risk prostate cancer
      • Within low-risk prostate tumors, higher DNA repair activity is associated with poor outcome
      • Within low-risk prostate patients who are candidates for active surveillance, high DNA repair activity defines a molecularly and clinically distinct subtype

      Abstract

      Introduction

      Understanding if divergent molecular profiles of DNA damage and repair (DDR) pathway activity, a biomarker of disease progression, exist in prostate tumors with favorable-risk features is an unmet need, which this study aim to unearth.

      Materials and Methods

      This was a multicenter registry genome-wide expression profiling study of prospectively collected radical prostatectomy (RP) tumor samples from 2014-2016. DDR activity was calculated from average expression of 372 DDR genes. Consensus hierarchical clustering was used to arrive at a robust clustering solution based on DDR gene expression patterns. Genome-wide differential expression between clusters was performed, and outcomes were evaluated across expression patterns.

      Results

      Of 5,239 patients from the prospective registry, 376 had favorable-risk disease (Grade group [GG] 1-2, PSA prior to RP <10ng/ml, pT2 or less). DDR activity score was correlated with prognostic genomic signatures that predict for metastatic risk (r=0.37, p<2e−16) and high grade groups (p<0.001). High DDR activity (top-quartile) was observed in 28% of patients with favorable-risk disease. In favorable-risk disease, three distinct clusters with varied DDR activity emerged with consensus clustering. Cluster I (compared with Cluster II-III and GG3-GG5 disease) had the highest expression of all DDR sub-pathways, MYC, PAPR1, AR, and AR activity (p<0.001 for all). Furthermore, Cluster I was associated with poorer metastasis-free survival (MFS) and Overall survival (OS) compared with other clusters (MFS; HR: 2.43, 95%CI [1.22-4.83], p=0.01; OS; HR: 2.77, 95%CI [1.18-6.5], p=0.01).

      Conclusions

      Cluster I is a novel subgroup of favorable-risk disease with high DDR activity, AR activity, PARP1 and chr8q/MYC expression, and poorer MFS and OS.
      Microabstract: DNA damage repair (DDR) pathways hold prognostic information in high-risk prostate cancer. Here, we investigated DDR in low-risk prostate cancer and demonstrated that high DDR is associated with poor clinical outcome and a distinct molecular subtype.

      Key Words

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