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The transcriptional landscape of endogenous retroelements delineates esophageal adenocarcinoma subtypes

Published version
Peer-reviewed

Repository DOI


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Authors

Kazachenka, Anastasiya 
Loong, Jane Hc 
Attig, Jan 
Young, George R 
Ganguli, Piyali 

Abstract

Most cancer types exhibit aberrant transcriptional activity, including derepression of retrotransposable elements (RTEs). However, the degree, specificity and potential consequences of RTE transcriptional activation may differ substantially among cancer types and subtypes. Representing one extreme of the spectrum, we characterize the transcriptional activity of RTEs in cohorts of esophageal adenocarcinoma (EAC) and its precursor Barrett's esophagus (BE) from the OCCAMS (Oesophageal Cancer Clinical and Molecular Stratification) consortium, and from TCGA (The Cancer Genome Atlas). We found exceptionally high RTE inclusion in the EAC transcriptome, driven primarily by transcription of genes incorporating intronic or adjacent RTEs, rather than by autonomous RTE transcription. Nevertheless, numerous chimeric transcripts straddling RTEs and genes, and transcripts from stand-alone RTEs, particularly KLF5- and SOX9-controlled HERVH proviruses, were overexpressed specifically in EAC. Notably, incomplete mRNA splicing and EAC-characteristic intronic RTE inclusion was mirrored by relative loss of the respective fully-spliced, functional mRNA isoforms, consistent with compromised cellular fitness. Defective RNA splicing was linked with strong transcriptional activation of a HERVH provirus on Chr Xp22.32 and defined EAC subtypes with distinct molecular features and prognosis. Our study defines distinguishable RTE transcriptional profiles of EAC, reflecting distinct underlying processes and prognosis, thus providing a framework for targeted studies.

Description

Funder: National Institutes of Health; DOI: https://doi.org/10.13039/100000002


Funder: NCI; DOI: https://doi.org/10.13039/501100002387


Funder: NHGRI; DOI: https://doi.org/10.13039/100000051


Funder: NHLBI; DOI: https://doi.org/10.13039/100000050


Funder: NIDA; DOI: https://doi.org/10.13039/100000026


Funder: NIMH; DOI: https://doi.org/10.13039/100000025


Funder: NINDS; DOI: https://doi.org/10.13039/100000065


Funder: Cancer Research UK; DOI: https://doi.org/10.13039/501100000289


Funder: UK Medical Research Council; DOI: https://doi.org/10.13039/501100000265


Funder: Wellcome Trust; DOI: https://doi.org/10.13039/100010269


Funder: European Research Council; DOI: https://doi.org/10.13039/100010663

Keywords

Journal Title

NAR Cancer

Conference Name

Journal ISSN

2632-8674

Volume Title

5

Publisher

Oxford University Press
Sponsorship
Francis Crick Institute (CC2088)
Horizon 2020 (101018670)