Cell-Free DNA Sequencing Reveals Gene Variants in DNA Damage Repair Genes Associated with Prognosis of Prostate Cancer Patients

Verena Lieb; Amer Abdulrahman; Katrin Weigelt; Siegfried Hauch; Michael Gombert; Juan Guzman; Laura Bellut; Peter J Goebell; Robert Stöhr; Arndt Hartmann; Bernd Wullich; Helge Taubert; Sven Wach

doi:10.3390/cells11223618

Cell-Free DNA Sequencing Reveals Gene Variants in DNA Damage Repair Genes Associated with Prognosis of Prostate Cancer Patients

Cells. 2022 Nov 15;11(22):3618. doi: 10.3390/cells11223618.

Authors

Verena Lieb^{1

2}, Amer Abdulrahman^{1

2}, Katrin Weigelt^{1

2}, Siegfried Hauch³, Michael Gombert³, Juan Guzman^{1

2}, Laura Bellut^{1

2}, Peter J Goebell^{1

2}, Robert Stöhr^{2

4}, Arndt Hartmann^{2

4}, Bernd Wullich^{1

2}, Helge Taubert^{1

2}, Sven Wach^{1

2}

Affiliations

¹ Department of Urology and Pediatric Urology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany.
² Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), 91054 Erlangen, Germany.
³ QIAGEN GmbH, 40724 Hilden, Germany.
⁴ Institute of Pathology, University Hospital Erlangen, FAU Erlangen-Nürnberg, 91054 Erlangen, Germany.

Abstract

In the present study, we further analyzed the data obtained in our previous study, where we investigated the cell-free DNA (cfDNA) of 34 progressive prostate cancer patients via targeted sequencing. Here, we studied the occurrence and prognostic impact of sequence variants according to their clinical pathological significance (CPS) or their functional impact (FI) in 23 DNA damage repair (DDR) genes with a focus on the ATM serine/threonine kinase gene (ATM). All patients had at least one DDR gene with a CPS or FI variant. Kaplan-Meier analysis indicated that the group with a higher number of CPS variants in DDR genes had a shorter time to treatment change (TTC) compared to the group with a lower number of CPS variants (p = 0.038). Analysis of each DDR gene revealed that CPS variants in the ATM gene and FI variants in the nibrin (NBN) gene showed a shorter TTC (p = 0.034 and p = 0.042). In addition, patients with CPS variants in the ATM gene had shorter overall survival (OS; p = 0.022) and disease-specific survival (DSS; p = 0.010) than patients without these variants. Interestingly, patients with CPS variants in seven DDR genes possessed a better OS (p = 0.008) and DSS (p = 0.009), and patients with FI variants in four DDR genes showed a better OS (p = 0.007) and DSS (p = 0.008). Together, these findings demonstrated that the analysis of cfDNA for gene variants in DDR genes provides prognostic information that may be helpful for future temporal and targeted treatment decisions for advanced PCa patients.

Keywords: ATM; DDR genes; NBN; cfDNA; prognosis; prostate cancer; sequence variants.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cell-Free Nucleic Acids*
DNA Damage / genetics
DNA Repair / genetics
Humans
Male
Prostatic Neoplasms* / genetics
Sequence Analysis, DNA

Substances

Cell-Free Nucleic Acids

Grants and funding

We would like to thank the Verein zur Förderung des Tumorzentrums der Universität Erlangen-Nürnberg e.V. for financial support of our project; the Deutsche Forschungsgemeinschaft (ID: TA 145/17-1) and the Rudolf and Irmgard Kleinknecht-Stiftung for supporting H.T.; and the Wilhelm Sander-Stiftung for supporting S.W. and H.T. (ID: 2015.171.1) We are grateful to the Deutsche Gesellschaft für Urologie (German Society of Urology) for supporting V.L. via a Ferdinand Eisenberger grant (ID: 14-07-11-1-Huppert).