Subtypes of Barrett's oesophagus and oesophageal adenocarcinoma based on genome-wide methylation analysis.

Gut
Authors
Keywords
Abstract

OBJECTIVE: To identify and characterise DNA methylation subtypes in oesophageal adenocarcinoma (EAC) and its precursor Barrett's oesophagus (BE).

DESIGN: We performed genome-wide DNA methylation profiling on samples of non-dysplastic BE from cancer-free patients (n=59), EAC (n=23), normal squamous oesophagus (n=33) and normal fundus (n=9), and identified methylation subtypes using a recursively partitioned mixture model. We assessed genomic alterations for 9 BE and 22 EAC samples with massively parallel sequencing of 243 EAC-associated genes, and we conducted integrative analyses with transcriptome data to identify epigenetically repressed genes. We also carried out in vitro experiments treating EAC cell lines with 5-Aza-2'-Deoxycytidine (5-Aza-dC), short hairpin RNA knockdown and anticancer therapies.

RESULTS: We identified and validated four methylation subtypes of EAC and BE. The high methylator subtype (HM) of EAC had the greatest number of activating events in (p

CONCLUSIONS: We identified and characterised methylator subtypes in BE and EAC. We further demonstrated the biological and clinical relevance of EAC methylator subtypes, which may ultimately help guide clinical management of patients with EAC.

Year of Publication
2019
Journal
Gut
Volume
68
Issue
3
Pages
389-399
Date Published
2019 03
ISSN
1468-3288
DOI
10.1136/gutjnl-2017-314544
PubMed ID
29884612
PubMed Central ID
PMC6565505
Links
Grant list
T32 DK007742 / DK / NIDDK NIH HHS / United States
P30 CA015704 / CA / NCI NIH HHS / United States
P50 CA150964 / CA / NCI NIH HHS / United States
U01 CA086402 / CA / NCI NIH HHS / United States
U01 CA182940 / CA / NCI NIH HHS / United States
P30 DK097948 / DK / NIDDK NIH HHS / United States
U01 CA152756 / CA / NCI NIH HHS / United States
U54 CA163060 / CA / NCI NIH HHS / United States