Multiple Myeloma Risk and Outcomes Are Associated with Pathogenic Germline Variants in DNA Repair Genes
First-degree relatives of patients with multiple myeloma are at increased risk for the disease, but the contribution of pathogenic germline variants (PGV) in hereditary cancer genes to multiple myeloma risk and outcomes is not well characterized. To address this, we analyzed germline exomes in two independent cohorts of 895 and 786 patients with multiple myeloma. PGVs were identified in 8.6% of the Discovery cohort and 11.5% of the Replication cohort, with a notable presence of high- or moderate-penetrance PGVs (associated with autosomal dominant cancer predisposition) in DNA repair genes (3.6% and 4.1%, respectively). PGVs in BRCA1 (OR = 3.9, FDR < 0.01) and BRCA2 (OR = 7.0, FDR < 0.001) were significantly enriched in patients with multiple myeloma when compared with 134,187 healthy controls. Five of the eight BRCA2 PGV carriers exhibited tumor-specific copy number loss in BRCA2, suggesting somatic loss of heterozygosity. PGVs associated with autosomal dominant cancer predisposition were associated with younger age at diagnosis, personal or familial cancer history, and longer progression-free survival after upfront high-dose melphalan and autologous stem-cell transplantation (P < 0.01). Significance: Our findings suggest up to 10% of patients with multiple myeloma may have an unsuspected cancer predisposition syndrome. Given familial implications and favorable outcomes with high-dose melphalan and autologous stem-cell transplantation in high-penetrance PGV carriers, genetic testing should be considered for young or newly diagnosed patients with a personal or family cancer history. See related commentary by Walker, p. 375.
Authors
- Hearn Jay Cho (ORCID: https://orcid.org/0000-0003-4481-5757)
- Oliver Van Oekelen (ORCID: https://orcid.org/0000-0002-5824-197X)
- Ajai Chari (ORCID: https://orcid.org/0000-0002-0405-7480)
- Meghana Ram
- Saoirse Bodnar (ORCID: https://orcid.org/0009-0006-7412-477X)
- Tehilla Brander (ORCID: https://orcid.org/0000-0002-2874-7777)
- Sundar Jagannath (ORCID: https://orcid.org/0000-0003-2934-6518)
- Joshua Ryan Richter (ORCID: https://orcid.org/0000-0002-0274-0585)
- Samir Sunil Parekh (ORCID: https://orcid.org/0000-0001-9694-8469)
- Cesar Rodriguez (ORCID: https://orcid.org/0009-0009-8240-5469)
- Scott Newman (ORCID: https://orcid.org/0000-0001-9309-4752)
- Erin Moshier (ORCID: https://orcid.org/0000-0002-8912-4709)
- Shambavi Richard (ORCID: https://orcid.org/0000-0003-0274-4292)
- Adriana Rossi (ORCID: https://orcid.org/0009-0004-9914-5628)
- Jane Houldsworth (ORCID: https://orcid.org/0000-0002-6781-1700)
- Tarek H. Mouhieddine (ORCID: https://orcid.org/0000-0002-1190-5978)
- Larysa Sanchez (ORCID: https://orcid.org/0000-0001-9353-7680)
- David T. Melnekoff (ORCID: https://orcid.org/0000-0003-2349-1917)
- Kenan Onel (ORCID: https://orcid.org/0000-0002-2021-6250)
- Santiago Thibaud (ORCID: https://orcid.org/0000-0001-8454-5136)
- Alessandro Laganà (ORCID: https://orcid.org/0000-0003-1134-0564)
- William Genthe (ORCID: https://orcid.org/0000-0002-5130-9345)
- Ryan L. Subaran
- Zachry Soens
Institutions
- Roswell Park Comprehensive Cancer Center (US)
- St. Jude Children's Research Hospital (US)
- University of California, San Francisco (US)
- Stamford Hospital (US)
- Sema4 (United States) (US)
- Tisch Hospital (US)
- Icahn School of Medicine at Mount Sinai (US)
Publication Details
- Journal
- Blood Cancer Discovery
- Published
- 2024-09-16
- DOI
- https://doi.org/10.1158/2643-3230.bcd-23-0208
- Citations
- 18
- Primary Topic
- Multiple Myeloma Research and Treatments
- Type
- article
- Field-Weighted Citation Impact
- 8.18
Funders
- Bristol-Myers Squibb Foundation
- Multiple Myeloma Research Foundation
- American Society of Hematology
- Bristol-Myers Squibb
- National Institutes of Health
- National Cancer Institute
- National Center for Advancing Translational Sciences