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.
Urologic oncology. 2021 Jul 26 [Epub ahead of print]
Cathleen Nientiedt, Jan Budczies, Volker Endris, Martina Kirchner, Constantin Schwab, Christina Jurcic, Rouven Behnisch, Shirin Hoveida, Philippa Lantwin, Adam Kaczorowski, Christine Geisler, Svenja Dieffenbacher, Fabian Falkenbach, Desiree Franke, Magdalena Görtz, Martina Heller, Ruth Himmelsbach, Carine Pecqueux, Mathias Rath, Philipp Reimold, Viktoria Schütz, Iva Simunovic, Elena Walter, Luisa Hofer, Claudia Gasch, Gita Schönberg, Lars Pursche, Gencay Hatiboglu, Joanne Nyarangi-Dix, Holger Sültmann, Stefanie Zschäbitz, Stefan A Koerber, Dirk Jäger, Jürgen Debus, Anette Duensing, Peter Schirmacher, Markus Hohenfellner, Albrecht Stenzinger, Stefan Duensing
Department of Medical Oncology, National Center for Tumor Diseases (NCT), University Hospital Heidelberg, Im Neuenheimer Feld 460, Heidelberg, Germany., Institute of Pathology, University Hospital Heidelberg, Im Neuenheimer Feld 224, Heidelberg, Germany., Molecular Urooncology, Department of Urology, University Hospital Heidelberg, Im Neuenheimer Feld 517, Heidelberg, Germany., Institute of Medical Biometry and Informatics, University of Heidelberg, Im Neuenheimer Feld 130, Heidelberg, Germany., Department of Urology, University Hospital Heidelberg, National Center for Tumor Diseases (NCT), Im Neuenheimer Feld 420, Heidelberg, Germany., Cancer Genome Research, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Im Neuenheimer Feld 460, Heidelberg, Germany., Department of Radiation Oncology, University Hospital Heidelberg, Im Neuenheimer Feld 400, Heidelberg, Germany., Cancer Therapeutics Program and Department of Pathology, University of Pittsburgh School of Medicine, UPMC Hillman Cancer Center, 5117 Centre Avenue, Pittsburgh, USA; Precision Oncology of Urological Malignancies, Department of Urology, University Hospital Heidelberg, Im Neuenheimer Feld 517, Heidelberg, Germany., Institute of Pathology, University Hospital Heidelberg, Im Neuenheimer Feld 224, Heidelberg, Germany. Electronic address: ., Molecular Urooncology, Department of Urology, University Hospital Heidelberg, Im Neuenheimer Feld 517, Heidelberg, Germany. Electronic address: .