Cis-regulatory somatic mutations and gene-expression alteration in B-cell lymphomas View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2015-12

AUTHORS

Anthony Mathelier, Calvin Lefebvre, Allen W Zhang, David J Arenillas, Jiarui Ding, Wyeth W Wasserman, Sohrab P Shah

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. More... »

PAGES

84

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  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1186/s13059-015-0648-7

    DOI

    http://dx.doi.org/10.1186/s13059-015-0648-7

    DIMENSIONS

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    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/25903198


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