Germline predisposition in multiple myeloma

Fernanda Martins Rodrigues, Jagoda Jasielec, Melody Perpich, Aelin Kim, Luke Moma, Yize Li, Erik Storrs, Michael C. Wendl, Reyka G. Jayasinghe, Mark Fiala, Andrew Stefka, Benjamin Derman, Andrzej J. Jakubowiak, John F. DiPersio, Ravi Vij, Lucy A. Godley*, Li Ding*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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 languageEnglish (US)
Article number111620
JournaliScience
Volume28
Issue number1
DOIs
StatePublished - 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

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