News
Article
Genetic Study Sheds Light on Inherited Risk of Multiple Myeloma
Author(s):
Approximately 10% of patients with multiple myeloma have pathogenic germline variants, indicating a hereditary risk.
Multiple myeloma (MM) had traditionally been considered not hereditary; however, emerging research suggests that there are familial risks to developing the disease. According to a genetic study, patients with MM are more likely to have inherited changes to pathogenic germline variants (PGVs) in the BRCA1, BRCA2, and other genes that increase cancer risk.
Blood cells | Image Credit: © Катерина Євтехова - stock.adobe.com
MM is an incurable, hematologic malignancy characterized by the uncontrolled growth of white blood cells, leading to renal failure, anemia, and brittle bones. Research shows that first-degree relatives of patients with MM have a 2- to 4-fold risk of MM or precursor conditions, as well as development of other solid and blood cancers. Sequencing studies have identified various rare, high-penetrance germline variants in families with MM, including CDKN2A, KDM1A, USP45, ARID1A, DIS3, and EP300. However, PGVs in known genes associated with hereditary cancer (HC) syndromes to MM risk have yet to be thoroughly described.
An estimated 3.9 million individuals harbor a PGV in high-risk genes in the United States, of which most are unaware of their cancer risk. PGVs are becoming more prevalent in a wide range of solid tumors and hematologic cancers, including those without a known genetic cause. For health care professionals and patients, identifying PGVs is extremely valuable because it can help determine the need for individualized screening and preventative measures. Furthermore, patients with PGVs who have been diagnosed with cancer may benefit from therapeutic implications.
The researchers evaluated germline exomes from patients with MM to characterize the contribution of PGVs in HC genes to the risk of MM. The patients were divided into 2 separate cohorts. The discovery cohort included 895 patients from the Multiple Myeloma Research Foundation's (MMRF) CoMMpass dataset compared with 786 patients from the Icahn School of Medicine at Mount Sinai (ISMMS) in the replication cohort. The median age at diagnosis across cohorts was 63 years (range, 25 to 94), of which 59% were male.
Across the 2 cohorts, PGVs were detected in approximately 10% of patients with MM. In the discovery cohort, 8.6% (77 of 895) of patients carried at least one PGV. A total of about 80 PGVs, representing 63 unique variants, were identified across 32 high-confidence genes, of which most were linked to DNA repair (81.3%), suggesting that defects in this process may contribute to MM development. The strongest associations were found in 2 key DNA repair pathways: homologous recombination, which repairs double-strand DNA breaks, and Fanconi anemia, a pathway that prevents DNA damage from accumulating.
In the replication cohort, 11.5% of patients were PGV carriers. The researchers found 95 heterozygous PGVs (73 unique variants) across 36 HC genes, of which 69.4% related to DNA repair. Homologous recombination (strength = 2.11, FDR = 1.65e−14) and Fanconi anemia (strength = 2.14, FDR = 8.76e−22) were the strongest pathway enrichments, which was also observed in the discovery group.
PGVs were found in 20 genes across both cohorts. The genes that were most frequently found to have high to moderate risk PGV (PGV-As) were ATM (n = 7; 2 in discovery, 5 in replication), CHEK2 (n = 8; 6 in discovery, 2 in replication), BRCA1 (n = 8; 1 in discovery, 7 in replication), and BRCA2 (n = 8; 4 in discovery, 4 replication). Of particular interest, DNA repair genes accounted for 95.3% of all PGV-As (100% in discovery, 91% in replication).
“Our study positions [MM] as a potential component of cancer-predisposing conditions associated with known HC genes, notably BRCA1/2,” the authors wrote. “The discovery of PGV-As in patients with [MM] not only highlights the importance of genetic testing for early detection and familial risk assessment but also opens up avenues for targeted therapeutic strategies that could significantly impact patient management and outcomes.”
These findings underscore the importance of genetic screening for patients with MM, as identifying PGVs could have significant clinical implications. Understanding the role of these inherited variants may help refine risk assessment, inform early detection strategies, and guide personalized treatment approaches, particularly for therapies targeting DNA repair deficiencies.
