Whole Genome Sequencing to Discover Familial Myeloma Risk Genes

We identified germline KDM1A truncating mutations in patients with multiple myeloma (MM), and loss of heterozygosity (LOH) in tumors. KDM1A mutation burden is higher in sporadic MM patients than in controls, and mRNA levels are lower in MM compared with normal plasma cells. KDM1A pharmacological inhibition in vitro promotes myeloma cell proliferation, and in mice promotes plasma cell expansion, enhanced secondary immune response to T cell dependent antigens, and upregulation of MYC oncogene transcriptional targets. Our findings provide important new insights into the role of KDM1A to suppress B cell malignancies.]]>
Familial MM probands that were analyzed by exome sequencing met the following inclusion criteria: Confirmed diagnosis that met the revised criteria of the International Myeloma Working Group, IgG heavy/light chain had been analyzed, and ≥ first-degree, or ≥ second-degree relatives diagnosed with MM. KDM1A-Sanger sequencing EA validation cohort (n=400) inclusion criteria were: (a-c) (N=200), or (a), (b) and (d) MM onset younger than age 60 (n=200). ]]>