Candidate Variants in DNA Replication and Repair Genes in Early-Onset Renal Cell Carcinoma Patients Referred for Germline Testing

Authors

Elena V. Demidova
Ilya G. Serebriiskii
Ramilia Vlasenkova
Simon Kelow
Mark D. Andrake
Tiffiney R. Hartman
Tatiana Kent, Thomas Jefferson UniversityFollow
James Virtucio
Gail L. Rosen
Richard T. Pomerantz, Thomas Jefferson UniversityFollow
Roland L. Dunbrack
Erica A. Golemis
Michael J. Hall
David Y.T. Chen
Mary B. Daly
Sanjeevani Arora

Document Type

Article

Publication Date

4-24-2023

Comments

This article is the author’s final published version in BMC Genomics, Volume 24, Issue 1, April 2023, Article number 212.

The published version is available at https://doi.org/10.1186/s12864-023-09310-8. Copyright © Demidova et al.

Abstract

Background: Early-onset renal cell carcinoma (eoRCC) is typically associated with pathogenic germline variants (PGVs) in RCC familial syndrome genes. However, most eoRCC patients lack PGVs in familial RCC genes and their genetic risk remains undefined.

Methods: Here, we analyzed biospecimens from 22 eoRCC patients that were seen at our institution for genetic counseling and tested negative for PGVs in RCC familial syndrome genes.

Results: Analysis of whole-exome sequencing (WES) data found enrichment of candidate pathogenic germline variants in DNA repair and replication genes, including multiple DNA polymerases. Induction of DNA damage in peripheral blood monocytes (PBMCs) significantly elevated numbers of [Formula: see text]H2AX foci, a marker of double-stranded breaks, in PBMCs from eoRCC patients versus PBMCs from matched cancer-free controls. Knockdown of candidate variant genes in Caki RCC cells increased [Formula: see text]H2AX foci. Immortalized patient-derived B cell lines bearing the candidate variants in DNA polymerase genes (POLD1, POLH, POLE, POLK) had DNA replication defects compared to control cells. Renal tumors carrying these DNA polymerase variants were microsatellite stable but had a high mutational burden. Direct biochemical analysis of the variant Pol δ and Pol η polymerases revealed defective enzymatic activities.

Conclusions: Together, these results suggest that constitutional defects in DNA repair underlie a subset of eoRCC cases. Screening patient lymphocytes to identify these defects may provide insight into mechanisms of carcinogenesis in a subset of genetically undefined eoRCCs. Evaluation of DNA repair defects may also provide insight into the cancer initiation mechanisms for subsets of eoRCCs and lay the foundation for targeting DNA repair vulnerabilities in eoRCC.

Recommended Citation

Demidova, Elena V.; Serebriiskii, Ilya G.; Vlasenkova, Ramilia; Kelow, Simon; Andrake, Mark D.; Hartman, Tiffiney R.; Kent, Tatiana; Virtucio, James; Rosen, Gail L.; Pomerantz, Richard T.; Dunbrack, Roland L.; Golemis, Erica A.; Hall, Michael J.; Chen, David Y.T.; Daly, Mary B.; and Arora, Sanjeevani, "Candidate Variants in DNA Replication and Repair Genes in Early-Onset Renal Cell Carcinoma Patients Referred for Germline Testing" (2023). Department of Biochemistry and Molecular Biology Faculty Papers. Paper 238.
https://jdc.jefferson.edu/bmpfp/238

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 License.

PubMed ID

37095444

Language

English