Journal Article

Candidate variants in DNA replication and repair genes in early-onset renal cell carcinoma patients referred for germline testing

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

2023

Overview

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 γ 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 γ 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.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Age / Analysis / Animal Genetics and Genomics / Biochemical analysis / Biomedical and Life Sciences / Cancer / Carcinogenesis / Carcinogens / Carcinoma, Renal Cell / Care and treatment / Cell cycle / Defects / Deoxyribonucleic acid / Diagnosis / DNA / DNA biosynthesis / DNA damage / DNA polymerase / DNA polymerases / DNA repair / DNA Replication / DNA-directed DNA polymerase / Enzymatic activity / Enzymes / Family medical history / Genes / Genetic aspects / Genetic counseling / Genetic Predisposition to Disease / Genetic research / Genetic screening / Genomes / Genomics / Germ Cells / Germ-Line Mutation / Germline / Health aspects / Humans / Kidney cancer / Kidney Neoplasms / Life Sciences / Lymphocytes / Methods / Microarrays / Microbial Genetics and Genomics / Monocytes / Ontology / Patients / Peripheral blood / Plant Genetics and Genomics / Proteomics / Renal cancer / Renal cell carcinoma / Replication / Risk assessment