Large-Scale Linkage Analysis of Multiple Myeloma (MM) and Monoclonal Gammopathy of Undetermined Significance (MGUS) Families

Abstract

Introduction Multiple myeloma (MM) is a result of a malignant transformation of plasma cells that is preceded by the presence of an asymptomatic clonal plasma cell expansion, a condition referred to as monoclonal gammopathy of undetermined significance (MGUS). We and others have shown familial aggregation of MM and MGUS. Evidence from epidemiologic, family and genome-wide association studies (GWAS) suggests a genetic component underlying MM etiology. GWAS have successfully established 17 common genetic risk loci for MM to date and recently, rare inherited susceptibility variants in the LSD1 / KDM1A and USP45 genes were identified in familial MM / MGUS kindreds. Family-based approaches may be used to elucidate genetic variation contributing to familial MM. Genetic linkage analysis has historically been used to detect the chromosomal location of disease genes. The objective of this study was to conduct a linkage analysis of MM / MGUS families to identify genomic regions for MM / MGUS. Methods Linkage analysis was performed on whole exome sequencing (WES) data generated from germline DNA extracted from peripheral blood from MM / MGUS families ascertained at four sites, of which 79 were selected with 2 or more affected members with any combination of MM or MGUS. Whole exome capture was performed using Agilent SureSelect 38 Mb paired end sequencing and ran on Illumina HiSeq 2000s/2500s; standard analyses for alignment (GRCh37) and quality control were conducted. The Genome Analysis Toolkit9s (GATK) HaplotypeCaller in per-sample mode was used to jointly call all the samples together. Quality control included removing variants that had Results Among the 79 families, 28 consisted of two or more MM, 41 had two or more MM and MGUS cases and 10 had two or more MGUS. Analyses of the 79 MM / MGUS families identified chromosome 6 at 123420001-149070000 BP region, with evidence for linkage by the non-parametric model (LOD score=3.3) and supportive evidence for linkage by the dominant parametric model (LOD=2.5) (Figure). The chromosome 6 region, which is outside the HLA-region, contains a total of 72 genes. Using gene-level association tests, we identified four genes within the region (MOXD1, TRDN, ADAT2, LTV1) that were associated within MM / MGUS in the family cases (p Discussion We found evidence for a locus on chromosome 6 linked to MM / MGUS. Four genes in this region may be associated with MM / MGUS in these families. Follow-up of these genes/variants in high-risk individuals (early-onset / age Disclosures Dumontet:Roche: Research Funding; Merck: Consultancy, Membership on an entity9s Board of Directors or advisory committees; Janssen: Honoraria; Sanofi: Honoraria. Kumar:AbbVie: Membership on an entity9s Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity9s Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity9s Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity9s Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity9s Board of Directors or advisory committees; Takeda: Membership on an entity9s Board of Directors or advisory committees; Merck: Membership on an entity9s Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity9s Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity9s Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Roche: Research Funding; Janssen: Membership on an entity9s Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity9s Board of Directors or advisory committees, Research Funding.