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GWAS Links Six New Loci to Multiple Myeloma Risk, Uncovers Potential Mechanisms

NEW YORK (GenomeWeb) – Through a new genome-wide association study and meta-analysis, researchers have linked six new loci to multiple myeloma risk.

In the US, there are an estimated 30,770 new multiple myeloma cases each year, and while some cases appear to be sporadic, others seem to have an inherited cause. Seventeen genetic loci have previously been linked to multiple myeloma risk.

Researchers from the Institute of Cancer Research in London and elsewhere conducted a genome-association study of nearly 900 multiple myeloma cases and more than 7,000 controls, which they combined with published data to uncover six new loci associated with multiple myeloma risk. As they reported today in Nature Communications, the researchers also found that these loci appear to disrupt developmental transcriptional regulators.

"Our study has identified six new areas of the genome that contribute to an increased risk of developing multiple myeloma, a type of blood cancer of which the biological basis has been relatively understudied," senior author Richard Houlston from ICR said in a statement. "Our increased understanding of the genetic background of myeloma has allowed us to start forming a clearer picture of the biology of the disease — which could open up new avenues for treatment."

Using the Illumina OncoArray chip, the researchers performed a GWAS of 878 multiple myeloma cases and 7,083 controls from the UK. They then combined their data with six other multiple myeloma GWAS datasets for a total of 7,319 cases and 234,385 controls. They replicated the nine loci they identified in a further set of 1,777 cases and 6,088 controls to ultimately link six new loci to multiple myeloma risk.

Based on a polygenic risk score they developed, the researchers estimated that the 23 new and known multiple myeloma risk loci account for about 16 percent of disease heritability. People falling in the top 1 percent of genetic risk for multiple myeloma have about a threefold increased risk of disease compared to those with median genetic risk, according to the researchers' estimate.

These 23 multiple myeloma risk loci tend to fall within noncoding regions and affect gene regulation, the researchers noted. Using ChIP-seq data generated on a multiple myeloma cell line in combination with naïve B-cell Blueprint Epigenome Project data, the researchers found that multiple myeloma-linked loci were enriched within areas of active chromatin as well as in B-cell transcription factor binding sites. This, they said, supports the notion that these risk loci could have their effects by influencing cis-regulatory networks involved in transcriptional initiation and enhancement.

With capture Hi-C and eQTL data, the researchers teased out four potential mechanisms through which these loci could work. Four risk loci, they noted, contain candidate genes linked to cell cycle regulation and genomic instability. Three other risk loci could be traced to candidate genes involved in chromatin remodeling, while five loci were linked with apoptosis or autophagy. Finally, they linked three loci to B cell and plasma cell differentiation and function.

"Increasing our knowledge of the complex pathways driving the development and progression of myeloma is going to be key to identifying new myeloma therapies, and to enable the tailoring of patient treatments," Simon Ridley, director of research at Myeloma UK, which funded the research, said in a statement.

The researchers cautioned, however, that their dataset and those they drew upon only included individuals of European ancestry. The effects of these risk SNPs may differ in African Americans, for instance, who have a high incidence of multiple myeloma, they noted.