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UBC Theses and Dissertations

Cis-regulatory somatic mutations and gene-expression alteration in B cell lymphomas Lefebvre, Calvin


Substantial progress has been achieved in characterizing protein coding (PC) regions for cancer genomes, with large contributions coming from The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC). In order to obtain a complete mutational profile of cancer genomes, the whole genome must be analyzed for two reasons: a large proportion of somatic mutations are within the non-coding region and 80% of the human genome is estimated to have some biological functionality. The dramatic cost reduction afforded by next generation sequencing has now made it tractable to sequence entire cancer genomes, allowing mutational profiling of the functional loci in the non-coding regions, such as cis-regulatory elements. Recent cancer genomic studies observed somatic mutations within cis-regulatory elements have the capacity to deregulate gene expression, but their impact remains underexplored. Initial attempts to prioritize cis-regulatory mutations did not incorporate RNASeq. We used 84 B cell lymphoma samples to address this limitation by prioritizing disruptive cis-regulatory mutations based on their potential to be the cause of observable cascading expression changes throughout biological networks. BCL6, ROBO1, GNA13, HAS2 and MYC were dysregulated genes targeted with somatic mutations through different mechanisms. Mutations either targeted the genes directly (PC mutations), indirectly (cis-regulatory mutations) or both. Our analyses demonstrates the importance of identifying genomically altered cis-regulatory elements, along with gene expression data, to interpret the mutational landscapes of cancers.

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