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Putative multiple myeloma susceptibility genes identified by exome sequencing of 347 familial and early-onset cases

Pertesi, Maroulio LU ; Demangel, Delphine ; Niroula, Abhishek LU ; Perrial, Emeline ; Mahecha Escobar, Maria Laura LU ; Vallée, Maxime ; Liacos, Christine ; Samur, Mehmet K ; Sperling, Adam S and Munshi, Nikhil C , et al. (2025) In Leukemia
Abstract

Multiple myeloma (MM) is the second most common blood malignancy, with several lines of evidence supporting an inherited genetic component. Here, we sequenced 177 affected individuals from 128 families, and 170 early-onset MM cases diagnosed before 55 years of age. Samples were identified and collected through nationwide efforts in France, Sweden, and Greece. We focused on rare germline protein truncating and likely deleterious missense variants in genes harboring variants in at least two families showing variant-disease segregation, and in additional index (≥2) and/or early-onset (≥2) cases. We identified likely pathogenic variants in ATM (N = 12), ANGPTL6 (N = 5), and FBXW9 (N = 6). Additionally, we detected variants in previously... (More)

Multiple myeloma (MM) is the second most common blood malignancy, with several lines of evidence supporting an inherited genetic component. Here, we sequenced 177 affected individuals from 128 families, and 170 early-onset MM cases diagnosed before 55 years of age. Samples were identified and collected through nationwide efforts in France, Sweden, and Greece. We focused on rare germline protein truncating and likely deleterious missense variants in genes harboring variants in at least two families showing variant-disease segregation, and in additional index (≥2) and/or early-onset (≥2) cases. We identified likely pathogenic variants in ATM (N = 12), ANGPTL6 (N = 5), and FBXW9 (N = 6). Additionally, we detected variants in previously reported MM predisposition genes, including DIS3, EP300, and KDM1A. Our results represent the largest sequencing study on familial and early-onset MM to date, and further illuminate the constitutional genetic basis of MM.

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publishing date
type
Contribution to journal
publication status
epub
subject
in
Leukemia
publisher
Nature Publishing Group
external identifiers
  • pmid:41254116
  • scopus:105022520967
ISSN
1476-5551
DOI
10.1038/s41375-025-02802-4
language
English
LU publication?
yes
id
00010d1e-2681-425f-88fe-6ffd726925ff
date added to LUP
2025-11-20 12:15:25
date last changed
2026-02-18 05:17:53
@misc{00010d1e-2681-425f-88fe-6ffd726925ff,
  abstract     = {{<p>Multiple myeloma (MM) is the second most common blood malignancy, with several lines of evidence supporting an inherited genetic component. Here, we sequenced 177 affected individuals from 128 families, and 170 early-onset MM cases diagnosed before 55 years of age. Samples were identified and collected through nationwide efforts in France, Sweden, and Greece. We focused on rare germline protein truncating and likely deleterious missense variants in genes harboring variants in at least two families showing variant-disease segregation, and in additional index (≥2) and/or early-onset (≥2) cases. We identified likely pathogenic variants in ATM (N = 12), ANGPTL6 (N = 5), and FBXW9 (N = 6). Additionally, we detected variants in previously reported MM predisposition genes, including DIS3, EP300, and KDM1A. Our results represent the largest sequencing study on familial and early-onset MM to date, and further illuminate the constitutional genetic basis of MM.</p>}},
  author       = {{Pertesi, Maroulio and Demangel, Delphine and Niroula, Abhishek and Perrial, Emeline and Mahecha Escobar, Maria Laura and Vallée, Maxime and Liacos, Christine and Samur, Mehmet K and Sperling, Adam S and Munshi, Nikhil C and Kastritis, Efstathios and Dimopoulos, Meletios A and McKay, James D and Mellqvist, Ulf-Henrik and Hansson, Markus and Dumontet, Charles and Nilsson, Björn}},
  issn         = {{1476-5551}},
  language     = {{eng}},
  month        = {{11}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Leukemia}},
  title        = {{Putative multiple myeloma susceptibility genes identified by exome sequencing of 347 familial and early-onset cases}},
  url          = {{http://dx.doi.org/10.1038/s41375-025-02802-4}},
  doi          = {{10.1038/s41375-025-02802-4}},
  year         = {{2025}},
}