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Multiple Myeloma Risk Genes Revealed Through Large Pedigree, Exome Analyses

NEW YORK (GenomeWeb) – An international team has uncovered two genes with apparent ties to inherited multiple myeloma risk, starting from analyses of several large American families that are frequently affected by the complex blood plasma cell cancer.

As they reported online today in PLOS Genetics, researchers from the US and France used an updated version of a gene mapping method known as shared genomic segment (SGS) to narrow in on commonly altered regions in the genomes of multiple myeloma-prone families — or "high-risk pedigrees" (HRP) — from Utah.

By folding in exome sequence data for nearly 1,000 myeloma-free individuals and more than 1,000 individuals affected by multiple myeloma or a precursor condition known as "monoclonal gammopathy of undetermined significance " (MGUS), the team went on to uncover suspicious changes in two genes, USP45 and ARID1A, that appeared to coincide with multiple myeloma risk.

"Exome sequencing of these genes revealed likely-damaging variants inherited in myeloma high-risk families, suggesting these genes likely play a role in development of myeloma," senior author Nicola Camp, a researcher at the University of Utah School of Medicine, and her colleagues wrote.

The team noted that family-based studies have proven invaluable for uncovering rare, causal mutations behind single-gene conditions, though it is often more difficult to pin down complex trait genetics using the pedigree-mapping approach alone.

"[W]hile HRPs have been successful for relatively simple traits," they wrote, "genetic heterogeneity remains a major obstacle that reduces the effectiveness of HRPs for gene mapping in complex traits."

With that in mind, the researchers looked for ways to whittle down on chromosomal regions of interest with a computational approach that tailored SGS mapping with genotyping insights from HRPs, while accounting for genetic heterogeneity in families.

Using Illumina OmniExpress high-density SNP arrays, they sequenced individuals from 11 multiple myeloma HRPs, identified through the Utah Cancer Registry, and applied SGS to find shared regions of the genome on chromosomes 6 and 1 with potential ties to multiple myeloma.

The team folded in exome sequence data for 28 individuals from the initial 11 pedigrees — along with 126 exomes from a broader set of 44 multiple myeloma pedigrees from the US, Canada, and France — to identify rare, potentially deleterious mutations in two genes falling the regions of interest: USP45 and ARID1A.

In an even wider exome sequence collection that encompassed 186 early onset multiple myeloma or familial MGUS cases, 733 cases of sporadic multiple myeloma profiled previously, and 964 unaffected controls, the investigators uncovered additional mutations affecting these genes or other genes falling in the same DNA repair or chromatin remodeling complex pathways as USP45 and ARID1A. 

"Our myeloma findings demonstrate our high-risk pedigree method can identify genetic regions of interest in large, high-risk pedigrees that are also relevant to smaller nuclear families and overall disease risk," Camp and her co-authors wrote, noting that "we have developed a strategy for gene mapping in complex traits that accounts for heterogeneity within HRPs and formally corrects for multiple testing to allow for statistically rigorous discovery."

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