Mutations in TP53 or DNA damage repair genes define poor prognostic subgroups in primary prostate cancer

• Published in: Urologic oncology Vol. 40; no. 1; pp. 8.e11 - 8.e18
• Main Authors: Nientiedt, Cathleen, Budczies, Jan, Endris, Volker, Kirchner, Martina, Schwab, Constantin, Jurcic, Christina, Behnisch, Rouven, Hoveida, Shirin, Lantwin, Philippa, Kaczorowski, Adam, Geisler, Christine, Dieffenbacher, Svenja, Falkenbach, Fabian, Franke, Desiree, Görtz, Magdalena, Heller, Martina, Himmelsbach, Ruth, Pecqueux, Carine, Rath, Mathias, Reimold, Philipp, Schütz, Viktoria, Simunovic, Iva, Walter, Elena, Hofer, Luisa, Gasch, Claudia, Schönberg, Gita, Pursche, Lars, Hatiboglu, Gencay, Nyarangi-Dix, Joanne, Sültmann, Holger, Zschäbitz, Stefanie, Koerber, Stefan A., Jäger, Dirk, Debus, Jürgen, Duensing, Anette, Schirmacher, Peter, Hohenfellner, Markus, Stenzinger, Albrecht, Duensing, Stefan
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-01-2022
• Subjects: Adult; Aged; BRCA1/2; DNA damage repair; DNA Repair - genetics; Humans; Male; Middle Aged; Mutation; Prognosis; Proof of Concept Study; Prostate cancer; Prostatic Neoplasms - genetics; TP53; Tumor Suppressor Protein p53 - genetics; DNA damage repair; BRCA1/2; Prostate cancer; TP53
• ISSN: 1078-1439; 1873-2496
• DOI: 10.1016/j.urolonc.2021.06.024

•We show that a substantial proportion of patients undergoing RPX for localized high-risk or locally advanced prostate cancer harbor mutations in DNA damage repair genes or TP53.•The presence of either a TP53 mutation or a mutation in a DNA damage repair gene conferred a significantly higher risk for a biochemical recurrence or PSA persistence.•TP53 and DNA damage repair gene mutations were not found to overlap in our patient cohort and an analysis of publicly available sequencing data showed that mutations in BRCA1/2 or ATM are enriched in TP53 wild-type tumors in two of three datasets.•Our findings underscore that mutations in TP53 or DNA damage repair genes can be detected in primary prostate cancer where they are associated with a more unfavorable prognosis. The significant negative impact on patient prognosis may be exploited to identify men with prostate cancer who may benefit from a more intensified treatment.
Mutations in DNA damage repair genes, in particular genes involved in homology-directed repair, define a subgroup of men with prostate cancer with a more unfavorable prognosis but a therapeutic vulnerability to PARP inhibition. In current practice, mutational testing of prostate cancer patients is commonly done late i.e., when the tumor is castration resistant. In addition, most sequencing panels do not include TP53, one of the most crucial tumor suppressor genes in human cancer. In this proof-of-concept study, we sought to extend the clinical use of these molecular markers by exploring the early prognostic impact of mutations in TP53 and DNA damage repair genes in men with primary, nonmetastatic prostate cancer undergoing radical prostatectomy (RPX).
Tumor specimens from a cohort of 68 RPX patients with intermediate (n = 11, 16.2%) or high-risk (n = 57, 83.8%) disease were analyzed by targeted next generation sequencing using a 37 DNA damage repair and checkpoint gene panel including TP53. Sequencing results were correlated to clinicopathologic variables as well as PSA persistence or time to PSA failure. In addition, the distribution of TP53 and DNA damage repair gene mutations was analyzed in three large publicly available datasets (TCGA, MSKCC and SU2C).
Of 68 primary prostate cancers analyzed, 23 (33.8%) were found to harbor a mutation in either TP53 (n = 12, 17.6%) or a DNA damage repair gene (n = 11, 16.2%). The vast majority of these mutations (22 of 23, 95.7%) were detected in primary tumors from patients with high-risk features. These mutations were mutually exclusive in our cohort and additional data mining suggests an enrichment of DNA damage repair gene mutations in TP53 wild-type tumors. Mutations in either TP53 or a DNA damage repair gene were associated with a significantly worse prognosis after RPX. Importantly, the presence of TP53/DNA damage repair gene mutations was an independent risk factor for PSA failure or PSA persistence in multivariate Cox regression models.
TP53 or DNA damage repair gene mutations are frequently detected in primary prostate cancer with high-risk features and define a subgroup of patients with an increased risk for PSA failure or persistence after RPX. The significant adverse impact of these alterations on patient prognosis may be exploited to identify men with prostate cancer who may benefit from a more intensified treatment.