Exome sequence comparison of seventy-seven multiple myeloma cases identifies potential risk alleles

Multiple Myeloma (MM) is a heritable cancer of plasma cells with poor prognosis. Although a few genomic risk-loci have been identified for MM, no risk variants have been published that explain MM heritability. We hypothesize MM heritability is due to rare germ-line variants that can be discovered through sequence comparison in high-risk MM cases. To uncover these rare risk-variants we sequenced the exomes (all protein-coding regions) of seventy-seven cases in high-risk pedigrees or diagnosed younger than usual. Alleles variant from a reference genome were prioritized based on sharing between cases and rarity in unaffected controls. Initial prioritization resulted in 7,344 variants which were further prioritized based on proximity to GWAS loci and effect on protein function. Six variants were within a thousand base pairs from a published GWAS locus. Of the six, an intronic SNP in CCND1 is of special interest as CCND1 is somatically altered in the tumors of 30% of MM cases and important in cell cycle progression. One hundred-nine variants were predicted to have high impact on protein function. Four of these variants were seen in additional samples including a frame-shift deletion in HAUS3. This variant is of special interest as HAUS3 regulates cell cycle progression in hematopoietic stem and progenitor cells. The potential risk-variants identified in this study demonstrate rare, genomic variants likely contribute to MM risk and can be identified through sequence comparison. These rare risk-variants could shed light on the genetic factors effecting MM and lead to eventual improved early detection and personalized treatment.