TY - JOUR
T1 - Germline predisposition in multiple myeloma
AU - Martins Rodrigues, Fernanda
AU - Jasielec, Jagoda
AU - Perpich, Melody
AU - Kim, Aelin
AU - Moma, Luke
AU - Li, Yize
AU - Storrs, Erik
AU - Wendl, Michael C.
AU - Jayasinghe, Reyka G.
AU - Fiala, Mark
AU - Stefka, Andrew
AU - Derman, Benjamin
AU - Jakubowiak, Andrzej J.
AU - DiPersio, John F.
AU - Vij, Ravi
AU - Godley, Lucy A.
AU - Ding, Li
N1 - Publisher Copyright:
© 2024
PY - 2025/1/17
Y1 - 2025/1/17
N2 - 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.
AB - 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.
KW - Cancer
KW - Genetics
KW - Molecular biology
UR - http://www.scopus.com/inward/record.url?scp=85213572094&partnerID=8YFLogxK
U2 - 10.1016/j.isci.2024.111620
DO - 10.1016/j.isci.2024.111620
M3 - Article
AN - SCOPUS:85213572094
SN - 2589-0042
VL - 28
JO - iScience
JF - iScience
IS - 1
M1 - 111620
ER -