Distinct Profiles of DNA Repair Activity Define Favorable-risk Prostate Cancer Subtypes With Divergent Outcome

Published:November 15, 2022DOI:

      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.



      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.


      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).


      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.


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        • D'Amico A.V.
        • Whittington R
        • Bruce-Malkowicz S
        • et al.
        Biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer.
        J Am Med Assoc. 1998; 280: 969-974
        • Hamdy FC
        • Donovan JL
        • Lane JA
        • et al.
        10-year outcomes after monitoring, surgery, or radiotherapy for localized prostate cancer.
        N Engl J Med. 2016; 375: 1415-1424
        • Mahal BA
        • Butler S
        • Franco I
        • et al.
        Use of active surveillance or watchful waiting for low-risk prostate cancer and management trends across risk groups in the United States, 2010-2015.
        J Urol. 2019; 202: 451-452
        • Loeb S
        • Byrne N
        • Makarov D.V.
        • Lepor H
        • Walter D.
        Use of conservative management for low-risk prostate cancer in the veterans affairs integrated health care system from 2005-2015.
        JAMA - J Am Med Assoc. 2018; 319: 2231-2233
        • Spratt D
        • Yousefi K
        • Deheshi S
        • et al.
        Individual patient-level meta-analysis of the performance of the decipher genomic classifier in high-risk men after prostatectomy to predict development of metastatic disease.
        JCO. 2017; 35: 1991-1998
        • Zhao S
        • Chang S
        • Erho N
        • et al.
        Associations of luminal and basal subtyping of prostate cancer with prognosis and response to androgen deprivation therapy.
        JAMA Oncol. 2017; 3: 1663-1672
        • Spratt DE
        • Zhang J
        • Santiago-Jimenez M
        • et al.
        Development and validation of a novel integrated clinical-genomic risk group classification for localized prostate cancer.
        JCO. 2018; 36: 581-590
        • Cooperberg MR
        • Erho N
        • Chan JM
        • et al.
        The diverse genomic landscape of clinically low-risk prostate cancer.
        Eur Urol. 2018; 74: 444-452
        • Evans JR
        • Zhao SG
        • Chang SL
        • et al.
        Patient-level DNA damage and repair pathway profiles and prognosis after prostatectomy for high-risk prostate cancer.
        JAMA Oncol. 2016; 2: 471-480
        • Carter HB
        • Helfand B
        • Mamawala M
        • et al.
        Germline mutations in ATM and BRCA1/2 are associated with grade reclassification in men on active surveillance for prostate cancer(Figure presented.
        Eur Urol. 2019; 75: 743-749
        • Ross AE
        • Johnson MH
        • Yousefi K
        • et al.
        Tissue-based genomics augments post-prostatectomy risk stratification in a natural history cohort of intermediate- and high-risk men.
        Eur Urol. 2016; 69: 157-165
        • Knijnenburg TA
        • Wang L
        • Zimmermann MT
        • et al.
        Genomic and molecular landscape of DNA damage repair deficiency across the cancer genome atlas.
        Cell Rep. 2018; 23 (e6): 239-254
        • Liberzon A
        • Birger C
        • Thorvaldsdttir H
        • Ghandi M
        • Mesirov JP
        • Tamayo P
        The molecular signatures database hallmark gene set collection.
        Cell Syst. 2015; 1: 417-425
        • Weiner AB
        • Liu Y
        • McFarlane M
        • et al.
        A transcriptomic model for homologous recombination deficiency in prostate cancer.
        Prostate Cancer Prostatic Dis. 2021;
        • Karanika S
        • Karantanos T
        • Li L
        • Corn PG
        • Thompson TC.
        DNA damage response and prostate cancer: Defects, regulation and therapeutic implications.
        Oncogene. 2015; 34: 2815-2822
        • Armenia J
        • Wankowicz SAM
        • Liu D
        • et al.
        The long tail of oncogenic drivers in prostate cancer.
        Nat Genet. 2018; 50: 645-651
        • Polkinghorn WR
        • Parker JS
        • Lee MX
        • et al.
        Androgen receptor signaling regulates DNA repair in prostate cancers.
        Cancer Discov. 2013; 3: 1245-1253
        • Goodwin JF
        • Schiewer MJ
        • Dean JL
        • et al.
        A hormone-DNA repair circuit governs the response to genotoxic insult.
        Cancer Discov. 2013; 3: 1254-1271
        • Ta HQ
        • Gioeli D.
        The convergence of DNA damage checkpoint pathways and androgen receptor signaling in prostate cancer.
        Endocr Relat Cancer. 2014; 21: R395-R407