Abstract
We present a study of rare germline predisposition variants in 954 unrelated individuals with multiple myeloma (MM) and 82 MM families. Using a candidate gene approach, we identified such variants across all age groups in 9.1% of sporadic and 18% of familial cases. Implicated genes included genes suggested in other MM risk studies as potential risk genes (DIS3, EP300, KDM1A, and USP45); genes involved in predisposition to other cancers (ATM, BRCA1/2, CHEK2, PMS2, POT1, PRF1, and TP53); and BRIP1, EP300, and FANCM in individuals of African ancestry. Variants were characterized using loss of heterozygosity (LOH), biallelic events, and gene expression analyses, revealing 31 variants in 3.25% of sporadic cases for which pathogenicity was supported by multiple lines of evidence. Our results suggest that the disruption of DNA damage repair pathways may play a role in MM susceptibility. These results will inform improved surveillance in high-risk groups and potential therapeutic strategies.
Original language | English (US) |
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Article number | 111620 |
Journal | iScience |
Volume | 28 |
Issue number | 1 |
DOIs | |
State | Published - Jan 17 2025 |
Funding
This work has been supported by the Paula C. and Rodger O. Riney Blood Cancer Research Initiative Fund to L.D. and R.V.; NCI U24CA211006 and R01HG009711 to L.D.; and V Foundation Grant FP067172 to L.A.G. We also thank the patients, families, and professionals who have contributed to the Multiple Myeloma Research Foundation CoMMpass Study, and the patients and families from the University of Chicago cohort for their continued engagement in research.
Keywords
- Cancer
- Genetics
- Molecular biology
ASJC Scopus subject areas
- General