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 to 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 5239 patients from the prospective registry, 376 had favorable-risk disease (Grade
group [GG] 1 to 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 < .001). High DDR activity (top-quartile) was observed in 28% of patients with favorable-risk
disease. In favorable-risk disease, 3 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 < .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 = .01; OS; HR: 2.77, 95%CI, [1.18-6.5], P = .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.
Keywords
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Article info
Publication history
Published online: November 15, 2022
Accepted:
November 8,
2022
Received in revised form:
November 6,
2022
Received:
September 1,
2022
Identification
Copyright
© 2022 Elsevier Inc. All rights reserved.
