High prevalence of DNA damage repair gene defects and TP53 alterations in men with treatment-naïve metastatic prostate cancer -Results from a prospective pilot study using a 37 gene panel.

Abstract

BACKGROUND:

Defects in DNA damage repair genes characterize a subset of men with prostate cancer and provide an attractive opportunity for precision oncology approaches. The prevalence of such perturbations in newly diagnosed, treatment-naïve patients with a high risk for lethal disease outcome, however, has not been sufficiently explored.

PATIENTS AND METHODS:

Prostate cancer specimens from 67 men with newly diagnosed early onset, localized high-risk/locally advanced or metastatic prostate cancer were included in this prospective pilot study. Tumor samples, including 30 prostate biopsies, were analyzed by targeted next generation sequencing using a formalin-fixed, paraffin-embedded tissue-optimized 37 DNA damage repair and checkpoint gene panel.

RESULTS:

The drop-out rate due to an insufficient quantity of DNA was 4.5% (3 of 67 patients). In the remaining 64 patients, the rate of pathogenic DNA damage repair gene mutations was 26.6%. The highest rate of pathogenic DNA damage repair and checkpoint gene mutations was found in men with treatment-naïve metastatic prostate cancer (38.9%). In addition, a high number of likely pathogenic mutations and gene deletions were detected. Altogether, one or more pathogenic mutation, likely pathogenic mutation or gene deletion affected 43 of 64 patients (67.2%) including 29 of 36 patients (80.6%) with treatment-naïve metastatic prostate cancer. Men with metastatic prostate cancer showed a high prevalence of alterations in TP53 (36.1%).

CONCLUSIONS:

This pilot study demonstrates the feasibility, performance and clinical relevance of somatic targeted next generation sequencing using a unique 37 DNA damage repair and checkpoint gene panel under routine conditions. Our results indicate that this approach can detect actionable DNA repair gene alterations, uncommon mutations as well as mutations associated with therapy resistance in a high number of patients, in particular patients with treatment-naïve metastatic prostate cancer.

• Authors: Cathleen Nientiedt, Volker Endris, Maximilian Jenzer, Josef Mansour, Nassim Tawanaie Pour Sedehi, Carine Pecqueux, Anna-Lena Volckmar, Jonas Leichsenring, Olaf Neumann, Martina Kirchner, Shirin Hoveida, Philippa Lantwin, Katrin Kaltenecker, Svenja Dieffenbacher, Claudia Gasch, Luisa Hofer, Desiree Franke, Georgi Tosev, Magdalena Görtz, Viktoria Schütz, Jan-Philipp Radtke, Joanne Nyarangi-Dix, Gencay Hatiboglu, Tobias Simpfendörfer, Gita Schönberg, Sanjay Isaac, Dogu Teber, Stefan A Koerber, Georgia Christofi, Elena Czink, Rebecca Kreuter, Leonidas Apostolidis, Clemens Kratochwil, Frederik Giesel, Uwe Haberkorn, Jürgen Debus, Holger Sültmann, Stefanie Zschäbitz, Dirk Jäger, Anette Duensing, Peter Schirmacher, Carsten Grüllich, Markus Hohenfellner, Albrecht Stenzinger, Stefan Duensing
• Journal: Urologic oncology (Urol Oncol) Vol. 38 Issue 7 Pg. 637.e17-637.e27 (07 2020) ISSN: 1873-2496 [Electronic] United States
• PMID: 32280037 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• TP53 protein, human
• Tumor Suppressor Protein p53

Topics

• Adult
• Aged
• Aged, 80 and over
• DNA Damage (genetics)
• DNA Repair (genetics)
• Humans
• Male
• Middle Aged
• Neoplasm Metastasis (genetics)
• Pilot Projects
• Prevalence
• Prospective Studies
• Prostatic Neoplasms (genetics, pathology)
• Treatment Outcome
• Tumor Suppressor Protein p53 (genetics)