Characterization of Rare Germline Variants in Familial Multiple Myeloma

Introduction: The risk of developing Multiple Myeloma (MM) is 2-4 fold higher in first-degree relatives of patients with MM compared to the general population, suggesting genetic predisposition to this cancer. Indeed, recent genome-wide association studies have identified common risk alleles that predispose for MM. Yet, the impact of these variants on MM risk is too low to explain familial aggregation of MM. High-impact alleles have been identified for other cancers such as ovarian and breast cancer (BRCA1,-2) and melanoma (CDKN2A) but the search for such alleles in MM is still in its infancy. In order to identify high-impact alleles in MM we have performed whole genome/exon sequencing (WGS/WES) in members of MM high risk families.

Methods: We included 21 families with multiple cases of MM/MGUS. Whole genome/exome sequencing was performed on a total of 46 affected and 20 unaffected family members. Filtering and prioritization of the variants were performed in accordance with the criteria of our in-house familial cancer variant prioritization pipeline version 2 (FCVPPv2). Loss-of-function variants were further screened using MutPred-LOF, Translate tool and IntOGen/c-BioPortal in order to discriminate pathogenic and neutral variants, to translate a nucleotide sequence to a protein sequence and to visualize the domain affected by the variant and the portion of the protein lost after the newly formed stop codon. Variants were analyzed for predicted effects on splicing by using Human Splicing Finder.

Results: We found a total of 148 potentially pathogenic variants, 109 non-synonymous and 39 LOF, in 18 out of 21 MM families. Among our genes, many affect protein metabolism, immune system, and other have known links to carcinogenesis. Additionally, some of them are known to interact with key signaling pathways in MM, including PI3K/Akt/mTOR, Ras/Raf/MEK/MAPK, JAK/STAT, NF-κB, Wnt/β-catenin, and RANK/RANKL/OPG, showing congruency with previously reported literature. Interestingly, we also found different missense variants in the same two genes in two unrelated families.

Conclusions: We have identified potentially pathogenic gene variants in 85% of MM/MGUS families. Our results can offer a useful reference to gene finding efforts by others in order to improve screening, early diagnosis and personalized therapy of individuals at risk of developing MM.