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Multiple Myeloma Study Links More Than Three Dozen Genes to Disease

NEW YORK (GenomeWeb) – Researchers have identified 40 genes that can be disrupted in the early stages of multiple myeloma.

While multiple myeloma is characterized by known recurrent chromosomal changes, how the disease first develops isn't clear. In 2017, there were 30,280 new multiple myeloma cases in the US and 12,590 deaths due to the disease, according to the National Cancer Institute.

Researchers from the Institute of Cancer Research in London examined whole-genome sequencing data from 765 patients with multiple myeloma. As they report in the journal Leukemia today, they uncovered coding and non-coding mutations that appear to drive the development of multiple myeloma, often by affecting the same biological pathways. These pathways, the researchers noted, could represent therapeutic targets.

"We need smarter, kinder treatments for myeloma that are more tailored to each person's cancer," senior author Richard Houlston, a professor of molecular and population genetics at ICR, said in a statement. "Exhaustive genetic research like this is helping us to make that possible. Our findings should now open up new avenues for discovering treatments that target the genes driving myeloma."

Houlston and his colleagues analyzed whole-exome sequencing data from 804 tumor-normal pairs and whole-genome sequencing data from 765 tumor-normal pairs from the Relating Clinical Outcomes in Multiple Myeloma to Personal Assessment of Genetic Profile (CoMMpass) study. Within the WGS data, they identified 71,573 mutations across the tumors.

Using the promoter capture Hi-C approach in naïve B-cells, they identified cis-regulatory elements (CREs) that could be affected by driver mutations in multiple myeloma. In particular, they uncovered 114 recurrently mutated CRE regions that interact with the promoters of 271 genes. These genes were overrepresented in pathways linked to cell adhesion, inflammatory response, NIK/NF-κB signaling, and the regulation of B-cell activation and differentiation, the researchers noted.

They also found that the genes targeted by of some of these recurrently mutated CREs had differing expression levels in mutated and non-mutated tumors. For instance, Houlston and his colleagues reported that recurrent mutations in the NBPF1 promoter were associated with increased expression of NBPF1, which is directly regulated by NF-κB. The NF-κB signaling pathway is recurrently altered in multiple myeloma, and the result suggested to the researchers that NBPF1 could be a novel candidate for involvement in multiple myeloma development.

They also reported six other recurrently mutated CREs linked to differential expression of their target genes, including the tumor suppressor PAX5, ST6GAL1, and HOXB2. Twenty-eight percent of tumors had mutations in at least one of the PAX5 CREs, they noted.

Copy number changes at CREs also affected gene expression, including at MYC, which is translocated in about 15 percent to 20 percent of multiple myeloma cases, but also at CREs interacting with PACS2, PLD4, and SP110, among others. The researchers noted that upregulation of MYC through gene amplification or translocation has been well established in multiple myeloma, and their finding indicates it can be dysregulated in other ways as well.

By folding in exome sequencing data from additional patients, the researchers found 33 genes that were significantly mutated, five of which were novel. Using the Reactome pathway analysis tool, they identified the pathways affected by these coding and non-coding mutations, which included MAPK signaling, NF-κB signaling, hematopoietic development, and apoptosis. A number of genes in these pathways were targeted by both coding and non-coding changes, the researchers reported, such as IRF4 and PRDM1.

The study has limited sensitivity, the researchers pointed out, but they were able to identify targets of non-coding mutations. While the results still need validation, the extended gene list could be mined for future therapies, they said.

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