Genetic and molecular characterization of mantle cell lymphoma

Despite advances in treatment and disease management, Mantle Cell Lymphoma (MCL) remains an incurable disease where patients typically succumb to the disease within 5 years of diagnosis. MCL is clinically and genetically a heterogenous disease which is reflected by the fact that there are two recognized subtypes: conventional MCL (cMCL) and non-nodal leukemic MCL (nnMCL), each thought to represent distinct evolutionary paths to lymphoma. Conventional MCL is also genetically and clinically heterogeneous where varying frequencies of simple somatic mutations, copy number variations and structural variations are observed across tumours. Conventional MCL can be robustly divided into three risk groups based on patient and histopathological parameters using the MIPI score, or by measuring gene expression of proliferation associated genes. In both cases, however, the underlying genetic cause for these clinical differences is largely unknown. In this thesis, I will begin by describing the integrative analysis where I used targeted sequencing, whole-genome sequencing, and RNA-sequencing to uncover novel driver genes. From analysing newly sequenced exomes along with published exomes, I uncovered recurrent mutations in HNRNPH1, EWSR1 and DAZAP1, thus implicating RNA-metabolism in MCL carcinogenesis. Furthermore, we validated the hypothesis that HNRNPH1 mutations serve to increase HNRNPH1 protein concentration by disrupting splicing of its own transcript. Next, using whole-genomes and RNA-sequencing, I found recurrent amplifications and structural variations on chromosome 10 that served to increase ABI1 expression. With this expanded catalogue of the genetic landscape of MCL, I applied non-negative matrix factorization to dissect cMCL and nnMCL cases into more refined subgroups. This resolved five genetic clusters that were prognostic for overall survival, progression-free survival, and disease-specific survival. This included the observations that within cMCL, patients with aberrant somatic hypermutation exhibited superior prognosis. In contrast, patients with harboured TERT amplifications, TP53 alterations or CCND1 3'UTR mutations had worse prognosis. This work has uncovered new genes that may form the basis for therapeutic intervention and delineates genetically-defined clinical subsets that could form the basis for applying personalized medicine in MCL.