title: Cis-regulatory somatic mutations and gene-expression alteration in B-cell lymphomas.
abstract: BACKGROUND
  With the rapid increase of whole-genome sequencing of human cancers, an important opportunity to analyze and characterize somatic mutations lying within cis-regulatory regions has emerged. A focus on protein-coding regions to identify nonsense or missense mutations disruptive to protein structure and/or function has led to important insights; however, the impact on gene expression of mutations lying within cis-regulatory regions remains under-explored. We analyzed somatic mutations from 84 matched tumor-normal whole genomes from B-cell lymphomas with accompanying gene expression measurements to elucidate the extent to which these cancers are disrupted by cis-regulatory mutations.
  
  
  RESULTS
  We characterize mutations overlapping a high quality set of well-annotated transcription factor binding sites (TFBSs), covering a similar portion of the genome as protein-coding exons. Our results indicate that cis-regulatory mutations overlapping predicted TFBSs are enriched in promoter regions of genes involved in apoptosis or growth/proliferation. By integrating gene expression data with mutation data, our computational approach culminates with identification of cis-regulatory mutations most likely to participate in dysregulation of the gene expression program. The impact can be measured along with protein-coding mutations to highlight key mutations disrupting gene expression and pathways in cancer.
  
  
  CONCLUSIONS
  Our study yields specific genes with disrupted expression triggered by genomic mutations in either the coding or the regulatory space. It implies that mutated regulatory components of the genome contribute substantially to cancer pathways. Our analyses demonstrate that identifying genomically altered cis-regulatory elements coupled with analysis of gene expression data will augment biological interpretation of mutational landscapes of cancers.
authors.affiliation: Department of Medical Genetics, Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, University of British Columbia, 950 West 28th Avenue, V5Z 4H4, Vancouver, BC, Canada. anthony.mathelier@gmail.com.
authors.forename: Anthony
authors.initials: A
authors.lastname: Mathelier
authors.affiliation: Department of Molecular Oncology, British Columbia Cancer Agency, Vancouver, V5Z 1L3, BC, Canada. clefebvre@bccrc.ca.|Bioinformatics Graduate Program, University of British Columbia, Vancouver, V5Z 1L3, BC, Canada. clefebvre@bccrc.ca.
authors.forename: Calvin
authors.initials: C
authors.lastname: Lefebvre
authors.affiliation: Department of Medical Genetics, Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, University of British Columbia, 950 West 28th Avenue, V5Z 4H4, Vancouver, BC, Canada. allenz9410@gmail.com.|Bioinformatics Graduate Program, University of British Columbia, Vancouver, V5Z 1L3, BC, Canada. allenz9410@gmail.com.
authors.forename: Allen W
authors.initials: AW
authors.lastname: Zhang
authors.affiliation: Department of Medical Genetics, Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, University of British Columbia, 950 West 28th Avenue, V5Z 4H4, Vancouver, BC, Canada. dave@cmmt.ubc.ca.
authors.forename: David J
authors.initials: DJ
authors.lastname: Arenillas
authors.affiliation: Department of Molecular Oncology, British Columbia Cancer Agency, Vancouver, V5Z 1L3, BC, Canada. jiaruid@cs.ubc.ca.|Department of Computer Science, University of British Columbia, Vancouver, V6T 1Z4, BC, Canada. jiaruid@cs.ubc.ca.
authors.forename: Jiarui
authors.initials: J
authors.lastname: Ding
authors.affiliation: Department of Medical Genetics, Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, University of British Columbia, 950 West 28th Avenue, V5Z 4H4, Vancouver, BC, Canada. wyeth@cmmt.ubc.ca.
authors.forename: Wyeth W
authors.initials: WW
authors.lastname: Wasserman
authors.affiliation: Department of Molecular Oncology, British Columbia Cancer Agency, Vancouver, V5Z 1L3, BC, Canada. sshah@bccrc.ca.|Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, G227-2211, BC, Canada. sshah@bccrc.ca.
authors.forename: Sohrab P
authors.initials: SP
authors.lastname: Shah
mesh_terms: D001665:Binding Sites; D019295:Computational Biology; D004252:DNA Mutational Analysis; D005091:Exons; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D056726:Genetic Association Studies; D015894:Genome, Human; D006801:Humans; D016393:Lymphoma, B-Cell / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D014157:Transcription Factors