Gamma-Retrovirus Integration Marks Cell Type-Specific Cancer Genes: A Novel Profiling Tool in Cancer Genomics.
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.
MRC-University of Glasgow Centre for Virus Research, Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom.
Kathryn L
KL
Gilroy
MRC-University of Glasgow Centre for Virus Research, Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom.
Anne
A
Terry
MRC-University of Glasgow Centre for Virus Research, Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom.
Asif
A
Naseer
Delft Bioinformatics Lab, Faculty of EEMCS, Delft University of Technology, Delft, The Netherlands.
Jeroen
J
de Ridder
Delft Bioinformatics Lab, Faculty of EEMCS, Delft University of Technology, Delft, The Netherlands.
Amin
http://orcid.org/0000-0003-2567-0273
A
Allahyar
Department of Biological Sciences, University of Alberta, Edmonton, Alberta, Canada.
Weiwei
W
Wang
Department of Biological Sciences, University of Alberta, Edmonton, Alberta, Canada.
Eric
E
Carpenter
Centre of Excellence for Gastrointestinal Inflammation and Immunity Research, University of Alberta, Edmonton, Alberta, Canada.
Andrew
A
Mason
Department of Biological Sciences, University of Alberta, Edmonton, Alberta, Canada.
Gane K-S
GK
Wong
MRC-University of Glasgow Centre for Virus Research, Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom.
Ewan R
http://orcid.org/0000-0001-8311-1491
ER
Cameron
MRC-University of Glasgow Centre for Virus Research, Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom.
Anna
A
Kilbey
MRC-University of Glasgow Centre for Virus Research, Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom.
James C
JC
Neil
D000818:Animals; D002415:Cats; D045744:Cell Line, Tumor; D002843:Chromatin / Q000235:genetics / Q000821:virology; D015972:Gene Expression Regulation, Neoplastic; D052138:Genes, Neoplasm; D006801:Humans; D005256:Leukemia Virus, Feline / Q000235:genetics*; D061986:MCF-7 Cells; D009369:Neoplasms / Q000235:genetics* / Q000821:virology*; D012192:Retroviridae Infections / Q000150:complications / Q000235:genetics / Q000821:virology*; D024363:Transcription Initiation Site; D014412:Tumor Virus Infections / Q000150:complications / Q000235:genetics / Q000821:virology*; D016662:Virus Integration
D002843:Chromatin