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Identification of subtypes of Barrett's esophagus and esophageal adenocarcinoma based on DNA methylation profiles and integration of transcriptome and genome data

Authors :
Timothy J. Underwood
Sujath Abbas
Rachel de la Rue
Jason Crawte
Juliane Perner
Richard C. Turkington
Paul A.W. Edwards
Sriganesh Jammula
Fergus Noble
Hugh Barr
Andy G. Lynch
Sari Suortamo
Catherine Harden
Vijayendran Sujendran
Maria Secrier
Sonia Puig
Sarah Oakes
Francesca D. Ciccarelli
Daniele Biasci
Monika Tripathi
Peter Safranek
Krishna Moorthy
Jim Davies
Constanza Linossi
Ula Mahadeva
Jan Bornschein
Richard Berrisford
Ted R. Hupp
Shaun R. Preston
Ayesha Noorani
Xiaodun Li
Michael Scott
Barbara Nutzinger
Annalise Katz-Summercorn
Neil A. Shepherd
Elwira Fidziukiewicz
Charles Crichton
Philippe Taniere
Adrienn Blasko
Amber Grantham
John H. Saunders
Michael P. Lewis
Caitriona Hughes
Ahmad Miremadi
Grant Sanders
Andrew D Beggs
Sharmila Sothi
Shona MacRae
Simon Tavaré
Ginny Devonshire
Sarah Killcoyne
Lawrence Bower
Christopher J. Peters
James A. Gossage
Shalini Malhotra
Laszlo Igali
Suzy Lishman
Philip Kaye
Simon L. Parsons
Alex Northrop
J. Robert O’Neill
Gianmarco Contino
Nicola Grehan
Maria O'Donovan
Olga Tucker
Elizabeth C Smyth
Yeng Ang
Irshad Soomro
Vinod V. Subash
Andrew Hindmarsh
Jesper Lagergren
Anna M. Grabowska
Izhar Bagwan
Andrew Davies
Rehan Haidry
Fuju Chang
Bhaskar Kumar
Jack Owsley
Rebecca C. Fitzgerald
Laurence Lovat
George B. Hanna
Matthew D. Eldridge
Stephen J. Hayes
J Zylstra
Vicky Goh
Richard J E Skipworth
Nick Carroll
Matthew Eldridge
Vicki Save
Ed Cheong
Filip Wronowski
Oliver Old
Biasci, Daniele [0000-0003-3148-8152]
Abbas, Sujath [0000-0002-2541-4969]
Eldridge, Matthew [0000-0002-5799-8911]
Apollo - University of Cambridge Repository
Source :
Gastroenterology
Publication Year :
2020

Abstract

BACKGROUND & AIMS: Esophageal adenocarcinomas (EACs) are heterogeneous and often preceded by Barrett's esophagus (BE). Many genomic changes have been associated with development of BE and EAC, but little is known about epigenetic alterations. We performed epigenetic analyses of BE and EAC tissues and combined these data with transcriptome and genomic data to identify mechanisms that control gene expression and genome integrity.METHODS: In a retrospective cohort study, we collected tissue samples and clinical data from 150 BE and 285 EAC cases from the Oesophageal Cancer Classification and Molecular Stratification consortium in the United Kingdom. We analyzed methylation profiles of all BE and EAC tissues and assigned them to subgroups using non-negative matrix factorization with k-means clustering. Data from whole-genome sequencing and transcriptome studies were then incorporated; we performed integrative methylation and RNA-sequencing analyses to identify genes that were suppressed with increased methylation in promoter regions. Levels of different immune cell types were computed using single-sample gene set enrichment methods. We derived 8 organoids from 8 EAC tissues and tested their sensitivity to different drugs.RESULTS: BE and EAC samples shared genome-wide methylation features, compared with normal tissues (esophageal, gastric, and duodenum; controls) from the same patients and grouped into 4 subtypes. Subtype 1 was characterized by DNA hypermethylation with a high mutation burden and multiple mutations in genes in cell cycle and receptor tyrosine signaling pathways. Subtype 2 was characterized by a gene expression pattern associated with metabolic processes (ATP synthesis and fatty acid oxidation) and lack methylation at specific binding sites for transcription factors; 83% of samples of this subtype were BE and 17% were EAC. The third subtype did not have changes in methylation pattern, compared with control tissue, but had a gene expression pattern that indicated immune cell infiltration; this tumor type was associated with the shortest time of patient survival. The fourth subtype was characterized by DNA hypomethylation associated with structure rearrangements, copy number alterations, with preferential amplification of CCNE1 (cells with this gene amplification have been reported to be sensitive to CDK2 inhibitors). Organoids with reduced levels of MGMT and CHFR expression were sensitive to temozolomide and taxane drugs.CONCLUSIONS: In a comprehensive integrated analysis of methylation, transcriptome, and genome profiles of more than 400 BE and EAC tissues, along with clinical data, we identified 4 subtypes that were associated with patient outcomes and potential responses to therapy.

Details

Language :
English
Database :
OpenAIRE
Journal :
Gastroenterology
Accession number :
edsair.doi.dedup.....912ceba758732d6d4584fa90151642b0