Cancer Predisposition Genes Found in 1 in 10 Patients With Multiple Myeloma
Approximately 10% of patients with multiple myeloma may have an unknown cancer predisposition syndrome, suggests a study published in Blood Cancer Discovery.
“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,” explained corresponding authors Samir Parekh, MD, of the Icahn School of Medicine at Mount Sinai, New York, and Kenan Onel, MD, PhD, of Roswell Park Comprehensive Cancer Center, Buffalo, New York, along with their coauthors in the study introduction.
To investigate PGVs in the patient population, researchers analyzed germline exomes in a total 1681 patients with multiple myeloma.
Among 895 patients from a discovery cohort from a Multiple Myeloma Research Foundation dataset, 8.6% of patients carried PGVs. Some 3.6% carried a high- or moderate-penetrance PGV, associated with autosomal dominant cancer predisposition in DNA repair genes, according to the study. In a replication cohort of 786 patients from the Icahn School of Medicine at Mount Sinai, 11.5% were PGV carriers, and 4.1% carried a high- or moderate-penetrance PGV associated with autosomal dominant cancer predisposition.
In a gene-specific burden analysis comparing patients from each cohort with 134,187 healthy controls, patients with multiple myeloma showed statistically significant enrichment of PGVs in BRCA1 and BRCA2 genes, researchers reported. Five of 8 patients who carried PGVs in BRCA2 showed tumor-specific copy number loss in BRCA2, suggestive of somatic loss of heterozygosity.
Patients at increased risk of carrying PGVs associated with autosomal dominant cancer predisposition had a younger age at diagnosis, a personal or family history of cancer, and longer progression-free survival after upfront high-dose melphalan and autologous stem cell transplantation, the study found.
“Taken together, our novel findings position multiple myeloma within the spectrum of malignancies influenced by hereditary genetic predispositions,” researchers wrote, “and support the integration of germline genetic testing into evaluations of patients with the disease.”
Reference
Thibaud S, Subaran RL, Newman S, et al. Multiple myeloma risk and outcomes are associated with pathogenic germline variants in DNA repair genes. Blood Cancer Discov. 2024;5(6):428-441. doi:10.1158/2643-3230.BCD-23-0208
