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Background <p>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).</p> Methods <p>Herein, we analyzed disease associations of pathogenic variations in nine putative candidate genes using 3 446 MM cases and 323 233 cancer-free controls.</p> Results <p>Increased MM risk was found to be associated with inherited rare pathogenic mutations in <i>TP53</i>,<i> ATM</i>,<i> CHEK2</i>,<i> KDM1A</i>,<i> and ARID1A</i>, with an enrichment of these variants among individuals with early onset or family history of MM. Individuals with <i>TP53</i> or <i>ATM</i> germline mutations are also likely to have worse overall survival.</p> Conclusions <p>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.</p>

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Multiple myeloma risk linked to DNA damage response genes

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年1月6日

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  • Michael Conry,
  • Irina Ostrovnaya,
  • Yelena Kemel,
  • Saloni Sinha,
  • Linda B. Baughn,
  • Brian Avery,
  • Kylee Maclachlan,
  • Victoria Groner,
  • Lauren Banaszak,
  • Aaron Norman,
  • Nicholas J. Boddicker,
  • Alyssa Clay-Gilmour,
  • Shaji Kumar,
  • Ellen Kim,
  • Sita Dandiker,
  • Mitul Waghmare,
  • Susan Slager,
  • Douglas W. Sborov,
  • Judy Garber,
  • Elizabeth E. Brown,
  • Michelle Hildebrandt,
  • Parameshwaran Hari,
  • Nicola Camp,
  • Celine Vachon,
  • Saad Usmani,
  • Kenneth Offit,
  • Vijai Joseph

摘要

Background

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).

Methods

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

Results

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.

Conclusions

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.