Gamma-retrovirus integration marks cell type-specific cancer genes: a novel profiling tool in cancer genomics

Gilroy, K. L. et al. (2016) Gamma-retrovirus integration marks cell type-specific cancer genes: a novel profiling tool in cancer genomics. PLoS ONE, 11(4), e0154070. (doi: 10.1371/journal.pone.0154070) (PMID:27097319) (PMCID:PMC4838236)

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Abstract

Retroviruses have been foundational in cancer research since early studies identified proto-oncogenes as targets for insertional mutagenesis. Integration of murine gamma-retroviruses into the host genome favours promoters and enhancers and entails interaction of viral integrase with host BET/bromodomain factors. We report that this integration pattern is conserved in feline leukaemia virus (FeLV), a gamma-retrovirus that infects many human cell types. Analysis of FeLV insertion sites in the MCF-7 mammary carcinoma cell line revealed strong bias towards active chromatin marks with no evidence of significant post-integration growth selection. The most prominent FeLV integration targets had little overlap with the most abundantly expressed transcripts, but were strongly enriched for annotated cancer genes. A meta-analysis based on several gamma-retrovirus integration profiling (GRIP) studies in human cells (CD34+, K562, HepG2) revealed a similar cancer gene bias but also remarkable cell-type specificity, with prominent exceptions including a universal integration hotspot at the long non-coding RNA MALAT1. Comparison of GRIP targets with databases of super-enhancers from the same cell lines showed that these have only limited overlap and that GRIP provides unique insights into the upstream drivers of cell growth. These observations elucidate the oncogenic potency of the gamma-retroviruses and support the wider application of GRIP to identify the genes and growth regulatory circuits that drive distinct cancer types.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Cameron, Professor Ewan and Neil, Professor James and Naseer, Dr Asif and Kilbey, Dr Anna and Gilroy, Dr Kathryn and Terry, Mrs Anne
Authors: Gilroy, K. L., Terry, A., Naseer, A., de Ridder, J., Allahyar, A., Wang, W., Carpenter, E., Mason, A., Wong, G. K.-S., Cameron, E. R., Kilbey, A., and Neil, J. C.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:PLoS ONE
Publisher:Public Library of Science
ISSN:1932-6203
ISSN (Online):1932-6203
Published Online:20 April 2016
Copyright Holders:Copyright © 2016 The Authors
First Published:First published in PLoS ONE 11(4): e0154070
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
539151New Approaches to Modelling Human LeukaemiaJames NeilCancer Research UK (CAN-RES-UK)11951MVLS III - CENTRE FOR VIRUS RESEARCH
539394New Approaches to Modelling Human LeukaemiaEwan CameronBloodwise (LLR)13046VET - PATHOLOGY, PUBLIC H & DISEASE INV