TY - JOUR
T1 - The transcriptional landscape of endogenous retroelements delineates esophageal adenocarcinoma subtypes
AU - Kazachenka, Anastasiya
AU - Loong, Jane Hc
AU - Attig, Jan
AU - Young, George R.
AU - Ganguli, Piyali
AU - Devonshire, Ginny
AU - Grehan, Nicola
AU - OCCAMS Consortium
AU - Ciccarelli, Francesca D.
AU - Fitzgerald, Rebecca C.
AU - Kassiotis, George
AU - Fitzgerald, Rebecca C.
AU - Edwards, Paul A.W.
AU - Grehan, Nicola
AU - Nutzinger, Barbara
AU - Fidziukiewicz, Elwira
AU - Redmond, Aisling M.
AU - Abbas, Sujath
AU - Freeman, Adam
AU - Smyth, Elizabeth C.
AU - O'Donovan, Maria
AU - Miremadi, Ahmad
AU - Malhotra, Shalini
AU - Tripathi, Monika
AU - Cheah, Calvin
AU - Coles, Hannah
AU - Flint, Connor
AU - Eldridge, Matthew
AU - Secrier, Maria
AU - Devonshire, Ginny
AU - Jammula, Sriganesh
AU - Davies, Jim
AU - Crichton, Charles
AU - Carroll, Nick
AU - Hardwick, Richard H.
AU - Safranek, Peter
AU - Hindmarsh, Andrew
AU - Sujendran, Vijayendran
AU - Hayes, Stephen J.
AU - Ang, Yeng
AU - Sharrocks, Andrew
AU - Preston, Shaun R.
AU - Bagwan, Izhar
AU - Save, Vicki
AU - Skipworth, Richard J.E.
AU - Hupp, Ted R.
AU - O'Neill, J. Robert
AU - Tucker, Olga
AU - Walker, Robert C.
AU - Hanna, George B.
AU - Petty, Russell D.
N1 - Publisher Copyright:
© 2023 The Author(s). Published by Oxford University Press on behalf of NAR Cancer.
PY - 2023/9/1
Y1 - 2023/9/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85168129035&partnerID=8YFLogxK
U2 - 10.1093/narcan/zcad040
DO - 10.1093/narcan/zcad040
M3 - Article
C2 - 37502711
AN - SCOPUS:85168129035
SN - 2632-8674
VL - 5
JO - NAR Cancer
JF - NAR Cancer
IS - 3
M1 - zcad040
ER -