The transcriptional landscape of endogenous retroelements delineates esophageal adenocarcinoma subtypes
Authors: Kazachenka Anastasiya , Loong Jane Hc , Attig Jan , Young George R , Ganguli Piyali , Devonshire Ginny , Grehan Nicola ,   The OCCAMS Consortium, Fitzgerald Rebecca C , Edwards Paul A W , Grehan Nicola , Nutzinger Barbara , Fidziukiewicz Elwira , Redmond Aisling M , Abbas Sujath , Freeman Adam , Smyth Elizabeth C , O’Donovan Maria , Miremadi Ahmad , Malhotra Shalini , Tripathi Monika , Cheah Calvin , Coles Hannah , Flint Connor , Eldridge Matthew , Secrier Maria , Devonshire Ginny , Jammula Sriganesh , Davies Jim , Crichton Charles , Carroll Nick , Hardwick Richard H , Safranek Peter , Hindmarsh Andrew , Sujendran Vijayendran , Hayes Stephen J , Ang Yeng , Sharrocks Andrew , Preston Shaun R , Bagwan Izhar , Save Vicki , Skipworth Richard J E , Hupp Ted R , O’Neill J Robert , Tucker Olga , Beggs Andrew , Taniere Philippe , Puig Sonia , Contino Gianmarco , Underwood Timothy J , Walker Robert C , Grace Ben L , Lagergren Jesper , Gossage James , Davies Andrew , Chang Fuju , Mahadeva Ula , Goh Vicky , Ciccarelli Francesca D , Sanders Grant , Berrisford Richard , Chan David , Cheong Ed , Kumar Bhaskar , Sreedharan L , Parsons Simon L , Soomro Irshad , Kaye Philip , Saunders John , Lovat Laurence , Haidry Rehan , Scott Michael , Sothi Sharmila , Lishman Suzy , Hanna George B , Peters Christopher J , Moorthy Krishna , Grabowska Anna , Turkington Richard , McManus Damian , Coleman Helen , Petty Russell D , Bartlett Freddie , Ciccarelli Francesca D , Fitzgerald Rebecca C , Kassiotis George 
Published: July 2023

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.