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Journal article
Candidate variants in DNA replication and repair genes in early-onset renal cell carcinoma patients referred for germline testing
BMC genomics, v 24(1), 212
24 Apr 2023
PMID: 37095444
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
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.
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.
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.
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.
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Details
- Title
- Candidate variants in DNA replication and repair genes in early-onset renal cell carcinoma patients referred for germline testing
- Creators
- Elena V Demidova - Fox Chase Cancer CenterIlya G Serebriiskii - Kazan Federal UniversityRamilia Vlasenkova - Kazan Federal UniversitySimon Kelow - University of PennsylvaniaMark D Andrake - Fox Chase Cancer CenterTiffiney R Hartman - Fox Chase Cancer CenterTatiana Kent - Thomas Jefferson UniversityJames Virtucio - Drexel UniversityGail L Rosen - Drexel UniversityRichard T Pomerantz - Thomas Jefferson UniversityRoland L Dunbrack, Jr - Fox Chase Cancer CenterErica A Golemis - Fox Chase Cancer CenterMichael J Hall - Fox Chase Cancer CenterDavid Y T Chen - Fox Chase Cancer CenterMary B Daly - Fox Chase Cancer CenterSanjeevani Arora - Fox Chase Cancer Center
- Publication Details
- BMC genomics, v 24(1), 212
- Publisher
- Springer BMC
- Number of pages
- 17
- Grant note
- P30 CA006927 / NCI NIH HHS R35 GM122517 / NIH HHS 1R01GM130889 / NIH HHS U01 CA164920 / NIH HHS R01 DK108195 / NIH HHS 1UH2CA271230-01 / NIH HHS
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Electrical and Computer Engineering
- Web of Science ID
- WOS:001188005900001
- Scopus ID
- 2-s2.0-85153687532
- Other Identifier
- 991020447127704721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Biotechnology & Applied Microbiology
- Genetics & Heredity