The University of British Columbia
B.Sc., Simon Fraser University, 2003
M.Sc., The University of British Columbia, 2007
Tuesday, December 12, 2011 at 12 PM
LOCATION: Lecture Theatre, BCCRC
Utilizing new sequencing technologies to identify somatic mutations in lymphoma and leukemia
Emerging “massively parallel” sequencing technologies offer opportunities to profile the genomes and transcriptomes of malignant cells for various types of somatic mutations and can also 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 and matched normal control samples for the purpose of identifying somatic point mutations and fusion transcripts. These and other tools were applied to gain insights into the somatic mutations driving two common classes of lymphoid malignancies, namely non Hodgkin lymphomas (NHLs) and acute lymphoblastic leukemia (ALL). Analysis of multiple cases of each disease with 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 responsible for in directing 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, demonstrated 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 ALL revealed both novel point mutations and fusion transcripts. The latter included fusions that appear to 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.
Supervisor: Dr. Marco Marra, Department of Medical Genetics, UBC