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Genetic variation in lymphocyte life and death genes and risk of non-Hodgkin lymphomas Schuetz, Johanna Maria


Background. Non-Hodgkin lymphomas (NHL) form a heterogeneous group of lymphocyte-derived solid tumors. Poor control of development and cell death in lymphocytes can lead to autoimmune disease, cancer and drug resistance. Lymphocyte development is a complex process marked by intense competition for nutrients, necessary DNA breaks and fast division times. BCL2, which controls apoptosis in lymphocytes, can be deregulated in diffuse large B-cell lymphoma (DLBCL) by the t(14;18) translocation and gene amplification. Methods. I surveyed genetic variation in 21 genes with roles in programmed cell death, lymphocyte development and DNA repair in constitutional DNA of NHL patients by gene re-sequencing. Genetic association tests for susceptibility to NHL subtypes were then conducted in a population-based collection of 797 NHL cases and 790 controls. I further studied BCL2 mutations in 491 tumors to investigate somatic mechanisms underlying lymphomagenesis. Results. 269 SNPs were discovered in constitutional DNA, 61% of which were novel. A few variants showed association with an NHL subtype, but most were not significant after correction for multiple tests. One variant near miR-155 was associated with marginal zone lymphoma (MZL). BCL2 is mutated in 60% of germinal centre B-cell like (GCB) DLBCL and in 85% of follicular lymphoma (FL); both arise from germinal centre B-cells and are characterized by t(14;18). The decreasing number of mutations with distance from the promoter and the enrichment of transitions over transversions imply that these mutations arise by somatic hypermutation. Many mutations are non-synonymous, and are rarely found in regions encoding BH domains. Other NHL subtypes, typically without t(14;18) and from different stages of development and lineages, showed very low levels of BCL2 mutations. 26% of DLBCL cases without detectable t(14;18) contained BCL2 mutations, indicating that mutations also occur by other mechanisms. Conclusions. These results strongly suggest that t(14;18) is important for acquiring additional BCL2 mutations in GCB-DLBCL and FL. The prevalence and the high number of mutations per sample suggest a selective advantage of BCL2 mutants in tumor development. Rs928883, near miR-155, is associated with increased risk of MZL. This is the first reported association between a miRNA-locus germline polymorphism and a subtype of non-Hodgkin lymphoma.

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