Results from a genome-wide association study (GWAS) provide insights into genetic predisposition for multiple myeloma (MM) and highlight causal mechanisms contributing to MM development. Molly Went, PhD, a postdoctoral fellow at the Institute of Cancer Research in London, and colleagues published their comprehensive analysis of the germline genetic architecture of MM in Nature Communications. Their findings point to two central biologic mechanisms mediating inherited MM risk: increased leukocyte telomere length (LTL) and increased B-cell maturation antigen (BCMA) and interleukin-5 receptor alpha (IL5RA) levels.
In their study, the investigators analyzed 10 GWAS datasets that included 10,906 cases and 366,221 controls and identified 35 MM risk loci, 12 of which were novel. They found support for the target genes in Cancer Dependency Map (DepMap) essentiality in MM or lymphoid cells, a Mendelian cancer predisposition syndrome, a congenital B-cell immunodeficiency, or recurrent somatic genetic lesions in MM.
“The associations between myeloma and these genetic variants represent quite modest increases in risk, but they are highly significant, replicate in further datasets, and appear to affect genes with a plausible role in disease,” Dr. Went said. Although the findings have only limited immediate clinical implications, she said, the work represents the most comprehensive investigation of how germline genetic variants influence myeloma risk. “We know there is a familial shared basis of myeloma, but we don’t have a really clear picture of how myeloma occurs,” she added.
To answer this question, the researchers integrated epigenetic and gene expression data to identify the most likely high-confidence causal gene at each locus associated with MM. For example, the researchers found that the risk variant rs34562254-A at TNFRSF13B mediated the largest increase in BCMA and IL5RA. Individuals with loss-of-function variants in TNFRSF13B developed B-cell immunodeficiency, but rs34562254-A exerted a gain-of-function effect, increasing MM risk via amplified B-cell response. Dr. Went said that identifying these high-confidence genes may benefit the broader research community and help identify new therapeutic options.
Myeloma is a late B-cell disease that can be classified into hyperdiploid and non-hyperdiploid subtypes. Non-hyperdiploid subtypes primarily comprise cases with immunoglobulin heavy chain (IGH) translocations that lead to overexpression of oncogenes CCNDA, MMSET, and MAF through juxtaposition with the IGH locus. In the current study, the investigators also found an association between MM and LTL and risk loci such as MYC, commonly associated with cancers.
“These common variations are sending these otherwise healthy cells on this route to becoming malignant,” Dr. Went said.
The study also included polygenic risk scores calculated based on effect sizes and allele frequencies in the five super-populations (European, American, African, East Asian, and South Asian). They observed the highest polygenic risk scores in the American super-population. Dr. Went explained that while such a score is not actionable, it may prove meaningful.
Monoclonal gammopathy of unknown significance (MGUS) typically precedes MM. The investigators examined the genetic overlap with other diseases by analyzing 6,234 MGUS cases and 720,279 controls. They found that glioma is also associated with LTL. The authors did not discuss their study’s limitations. They concluded their findings by proposing a model in which MM predisposition stems from dysregulation of telomere maintenance, B-cell development, and plasma cell development.
Any conflicts of interest declared by the authors can be found in the original article.
Reference
Went M, Duran-Lozano L, Halldorsson GH, et al. Deciphering the genetics and mechanisms of predisposition to multiple myeloma. Nat Commun. 2024;15(1):6644.
