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Mutation discovery and characterization in lymphoid neoplasms using massively parallel RNA and DNA sequencing Morin, Ryan David


New massively parallel sequencing technologies offer opportunities to profile genomes and transcriptomes for copy number variations, polymorphisms, somatic point mutations, chromosomal rearrangements and can capture gene expression and splicing information. A suite of methods was developed to analyze both RNA-seq and whole genome/exome sequence data from malignant cells for the purpose of identifying somatic point mutations and fusion transcripts. This work reports the application of these and other tools to gain insights into the somatic mutations involved in two common classes of lymphoid malignancies, namely non Hodgkin lymphoma and acute lymphoblastic leukemia. Analysis of multiple cases by a combination of RNA-seq, genome and exome sequencing revealed genes significantly mutated in non Hodgkin lymphoma including many not previously known to be mutated in these or any other cancers. These included multiple genes involved in altering the methylation or acetylation state of histones such as EZH2, MLL2, CREBBP and MEF2B, suggesting a previously unappreciated role of deregulated or altered epigenetic gene regulation in lymphomagenesis. Some of the mutated genes, such as MLL2, had clear patterns of inactivating mutations, indicating they act as tumour suppressors in NHL. Others had mutation hot spots that can be indicative of an oncogenic gain of function and this was proven to be the case for the mutation hot spot identified in EZH2. Analysis of acute lymphoblastic leukemia revealed both novel point mutations and fusion transcripts. The latter included fusions that potentially deregulate known oncogenes such as JAK2 and ABL1. These data may indicate new treatment options for patients with ALL and NHL and lend new insights into the molecular nature of these diseases.

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