Multiple myeloma risk linked to DNA damage response genes

TL;DR

This study finds that inherited DNA damage response gene mutations increase the risk of multiple myeloma, especially in those with early onset or family history.

Contribution

The study identifies new germline risk genes for multiple myeloma and suggests targeted screening for high-risk individuals.

Findings

Rare pathogenic mutations in TP53, ATM, CHEK2, KDM1A, and ARID1A are linked to increased multiple myeloma risk.

TP53 or ATM germline mutations are associated with worse overall survival in multiple myeloma patients.

These DDRG mutations are enriched in individuals with early-onset or familial multiple myeloma.

Abstract

DNA damage response genes (DDRG), implicated in several cancers as both predisposing risk factors as well as biomarkers for aggressiveness, have not been fully explored in multiple myeloma (MM).

Herein, we analyzed disease associations of pathogenic variations in nine putative candidate genes using 3 446 MM cases and 323 233 cancer-free controls.

Increased MM risk was found to be associated with inherited rare pathogenic mutations in TP53, ATM, CHEK2, KDM1A, and ARID1A, with an enrichment of these variants among individuals with early onset or family history of MM. Individuals with TP53 or ATM germline mutations are also likely to have worse overall survival.

Our results suggest expansion of the phenotypic spectrum of some of these DDRG to include MM. The identification of these germline predisposition genes opens the avenue for targeted screening of higher risk individuals especially those with young-onset or a family history of plasma cell gammopathies.

The online version contains supplementary material available at 10.1186/s13045-025-01776-1.

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