UBC Theses and Dissertations
Mantle cell lymphoma pathogenesis deLeeuw, Ronald John
Mantle cell lymphoma (MCL) is an aggressive non-Hodgkin’s lymphoma with a median patient survival time of 3 years. Although the characteristic t(11;14)(q13;q32) is found in virtually all cases, experimental evidence suggests that this event alone is insufficient to result in lymphoma and secondary genomic alterations are required. Therefore, secondary genetic alterations have been proposed as essential in MCL pathogenesis. Within this thesis I describe the creation of a novel assay to determine segmental copy number alterations at a previously unprecedented resolution. This new assay necessitated the development of new analytical software to visualize and analyze the high density data sets created. The creation of this software is described in detail. With these tools in place we assayed model genomes of MCL for recurrent segmental copy number alterations. These recurrent regions were defined; however, among these were copy number variations that appeared in both cases and controls. Investigation of these natural copy number variations in this thesis revealed that the human genome has a higher plasticity than previously appreciated. In fact, thousands of loci within the genome were found to be variable in copy number that may influence sensory perception and possibly disease susceptibility. I next investigated the genomes of MCL tumor samples to determine which somatic copy number alterations are related to a poor clinical course. Among the numerous loci that showed frequent copy number alterations in MCL genomes, many were associated with poor patient outcome. Among these, the loss of 9p21 was a strong factor in determining the clinical course of patients with MCL (P=0.0004). Three additional loci (4q13, 8q24, and 13q14) were combined with 9p21 to create a survival model that was very predictive of patient outcome (P=5.87 x 10-6). Interestingly, a previously uncharacterized locus (4q13) was within this survival model. Investigating this locus further revealed that the expression of two genes (CCNG2 and CCNI) influences the overall survival of patients with MCL (P=0.0292 and 0.0201, respectively).
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