Identification of a primitive intestinal transcription factor network shared between esophageal adenocarcinoma and its precancerous precursor state

Connor Rogerson, Edward Britton, Sarah Withey, Neil Hanley, Yeng S. Ang*, Andrew D. Sharrocks

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

28 Citations (Scopus)

Abstract

Esophageal adenocarcinoma (EAC) is one of the most frequent causes of cancer death, and yet compared to other common cancers, we know relatively little about the molecular composition of this tumor type. To further our understanding of this cancer, we have used open chromatin profiling to decipher the transcriptional regulatory networks that are operational in EAC. We have uncovered a transcription factor network that is usually found in primitive intestinal cells during embryonic development, centered on HNF4A and GATA6. These transcription factors work together to control the EAC transcriptome. We show that this network is activated in Barrett’s esophagus, the putative precursor state to EAC, thereby providing novel molecular evidence in support of stepwise malignant transition. Furthermore, we show that HNF4A alone is sufficient to drive chromatin opening and activation of a Barrett’s-like chromatin signature when expressed in normal human epithelial cells. Collectively, these data provide a new way to categorize EAC at a genome scale and implicate HNF4A activation as a potential pivotal event in its malignant transition from healthy cells.

Original languageEnglish
Pages (from-to)723-736
Number of pages14
JournalGenome Research
Volume29
Issue number5
DOIs
Publication statusPublished - May 2019

Bibliographical note

Funding Information:
We thank Mairi Challinor for excellent technical assistance, Frances Sladek and Kevin Janes for reagents, and staff in the Genomic Technologies and Bioinformatics Core Facilities. We also thank Munazah Andrabi for bioinformatics advice and guidance, and Dave Gerrard for the analysis of human embryonic RNA-seq data sets. We also thank James Britton for collection of Barrett’s esophagus samples. We thank Xiaodun Li and Rebecca Fitzgerald on behalf of the Oesophageal Cancer Clinical and Molecular Stratification (OCCAMS) Consortium for the normal and tumor sample collection. We also thank Shen-Hsi Yang, Dave Gerrard, and Nicoletta Bobola for critical appraisal of the manuscript. This work was funded by grants from the Wellcome Trust (103857/Z/14/Z), Cancer Research UK (through the Manchester Cancer Research Centre), and a Medical Research Council Doctoral Training Partnership studentship to S.W.

Publisher Copyright:
© 2019 Rogerson et al.

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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