title: Comparative transcriptome analysis of isogenic cell line models and primary cancers links capicua (CIC) loss to activation of the MAPK signalling cascade.
abstract: CIC encodes a transcriptional repressor, capicua (CIC), whose disrupted activity appears to be involved in several cancer types, including type I low-grade gliomas (LGGs) and stomach adenocarcinomas (STADs). To explore human CIC's transcriptional network in an isogenic background, we developed novel isogenic CIC knockout cell lines as model systems, and used these in transcriptome analyses to study the consequences of CIC loss. We also compared our results with analyses of transcriptome data from TCGA for type I LGGs and STADs. We identified 39 candidate targets of CIC transcriptional regulation, and confirmed seven of these as direct targets. We showed that, although many CIC targets appear to be context-specific, the effects of CIC loss converge on the dysregulation of similar biological processes in different cancer types. For example, we found that CIC deficiency was associated with disruptions in the expression of genes involved in cell-cell adhesion, and in the development of several cell and tissue types. We also showed that loss of CIC leads to overexpression of downstream members of the mitogen-activated protein kinase (MAPK) signalling cascade, indicating that CIC deficiency may present a novel mechanism for activation of this oncogenic pathway. © 2017 The Authors. Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
authors.affiliation: Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, Canada.|Genome Science and Technology Program, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Veronique G
authors.initials: VG
authors.lastname: LeBlanc
authors.affiliation: Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, Canada.
authors.forename: Marlo
authors.initials: M
authors.lastname: Firme
authors.affiliation: Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, Canada.
authors.forename: Jungeun
authors.initials: J
authors.lastname: Song
authors.affiliation: Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, Canada.
authors.forename: Susanna Y
authors.initials: SY
authors.lastname: Chan
authors.affiliation: Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, Canada.
authors.forename: Min Hye
authors.initials: MH
authors.lastname: Lee
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia, BC, Canada.
authors.forename: Stephen
authors.initials: S
authors.lastname: Yip
authors.affiliation: Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, Canada.
authors.forename: Suganthi
authors.initials: S
authors.lastname: Chittaranjan
authors.affiliation: Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, Canada.|Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Marco A
authors.identifier: 0000-0001-7146-7175
authors.initials: MA
authors.lastname: Marra
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics*; D045744:Cell Line, Tumor; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D055786:Gene Knockout Techniques; D005910:Glioma / Q000235:genetics*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000235:genetics*; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics*; D013274:Stomach Neoplasms / Q000235:genetics*; D059467:Transcriptome
chemical_list: C498610:CIC protein, human; D012097:Repressor Proteins; D020928:Mitogen-Activated Protein Kinases
keywords: MAPK signalling; capicua; glioma; stomach adenocarcinoma