Identification and characterization of DNA sequence variants associated with multiple myeloma

Sammanfattning: Multiple myeloma (MM) is the second most common hematologic malignancy. The disease is characterized by an uncontrolled growth of malignant plasma cells in the bone marrow, producing a monoclonal immunoglobulin (“M protein”) that can be detected in peripheral blood. Clinically, MM is characterized by bone marrow failure, lytic bone lesions, hypercalcemia, and kidney failure. It is preceded by monoclonal gammopathy of unknown significance (MGUS), a common condition defined as a clonal growth of plasma cells that does not yet satisfy the criteria for MM, but progresses to MM at a rate of 1% per year. Increasing evidence supports that the biology of MM is influenced by inborn genetic variation and first degree relatives of patients with MM and MGUS seem to have higher risk for MM, and a higher risk of certain other malignancies. In this Ph.D. project, we aim to find DNA sequence variants that predispose for MM, and understand how these variants contribute to MM development.Case-control genome-wide association study (GWAS) is our approach for finding variants. Previous GWASes have identified eight genetic variants that associate with MM development. As a first step in this study, we also carried out a GWAS on a case-control data set from Sweden-Norway and Iceland (Paper I). Following statistical analysis we could identify one novel MM risk locus related to the ELL2 (Elongation Factor for RNA Polymerase II 2) gene and a promising association with the TOM1-HMGXB4 locus at 22q13 and we could confirm the previously reported loci. In the second part of the project, we carried out a meta-analysis of six genome-wide association studies together with the United Kingdom, Germany, Netherlands, the United States and Iceland. Previously reported loci were confirmed and eight new loci were discovered (Paper II). Understanding how the identified risk variants contribute to MM development is the next challenge. In the third part of the project we focused on the ELL2 gene located on the locus 5q15 and tried to understand its mechanism of action in MM (Paper III). Finally, we retrieved clinical information for 871 patients diagnosed with MM from the Swedish Multiple Myeloma Registry. We tested for association between sequence variants and MM overall survival (Paper IV). Our findings provide further insights into the genetic and biological basis of MM predisposition.