Novel Aberrations Uncovered in Barrett's Esophagus and Esophageal Adenocarcinoma Using Whole Transcriptome Sequencing.

Jesper L.V Maag,David I Watson,Melanie Edwards,Marcel E Dinger,Damian J Hussey,Yuri V Bobryshev,Antony Wettstein,Dominik C Kaczorowski,Oliver M Fisher,Angelique Levert-Mignon,Reginald V Lord,Melissa L Thomas

doi:10.1158/1541-7786.mcr-17-0332

Abstract

Esophageal adenocarcinoma (EAC) has one of the fastest increases in incidence of any cancer, along with poor five-year survival rates. Barrett's esophagus (BE) is the main risk factor for EAC; however, the mechanisms driving EAC development remain poorly understood. Here, transcriptomic profiling was performed using RNA-sequencing (RNA-seq) on premalignant and malignant Barrett's tissues to better understand this disease. Machine-learning and network analysis methods were applied to discover novel driver genes for EAC development. Identified gene expression signatures for the distinction of EAC from BE were validated in separate datasets. An extensive analysis of the noncoding RNA (ncRNA) landscape was performed to determine the involvement of novel transcriptomic elements in Barrett's disease and EAC. Finally, transcriptomic mutational investigation of genes that are recurrently mutated in EAC was performed. Through these approaches, novel driver genes were discovered for EAC, which involved key cell cycle and DNA repair genes, such as BRCA1 and PRKDC. A novel 4-gene signature (CTSL, COL17A1, KLF4, and E2F3) was identified, externally validated, and shown to provide excellent distinction of EAC from BE. Furthermore, expression changes were observed in 685 long noncoding RNAs (lncRNA) and a systematic dysregulation of repeat elements across different stages of Barrett's disease, with wide-ranging downregulation of Alu elements in EAC. Mutational investigation revealed distinct pathways activated between EAC tissues with or without TP53 mutations compared with Barrett's disease. In summary, transcriptome sequencing revealed altered expression of numerous novel elements, processes, and networks in EAC and premalignant BE.Implications: This study identified opportunities to improve early detection and treatment of patients with BE and esophageal adenocarcinoma. Mol Cancer Res; 15(11); 1558-69. ©2017 AACR.

Highlights

Esophageal adenocarcinoma (EAC) has one of the fastest increases in incidence rates of all cancers since the 1970s in white populations of all age groups in many countries [1, 2].Note: Supplementary data for this article are available at Molecular Cancer Research Online.J.L.V
Enrichment for the immune cell score was only observed in EAC, possibly indicating a higher percentage of immune cell infiltration in EAC compared with Barrett's esophagus (BE) (Supplementary Fig. S1C)
Our investigation of the noncoding RNA landscape and assessment of expressed gene mutations have identified new processes involved in the development of this disease

Summary

Introduction

Esophageal adenocarcinoma (EAC) has one of the fastest increases in incidence rates of all cancers since the 1970s in white populations of all age groups in many countries [1, 2].Note: Supplementary data for this article are available at Molecular Cancer Research Online (http://mcr.aacrjournals.org/).J.L.V. Esophageal adenocarcinoma (EAC) has one of the fastest increases in incidence rates of all cancers since the 1970s in white populations of all age groups in many countries [1, 2]. Note: Supplementary data for this article are available at Molecular Cancer Research Online (http://mcr.aacrjournals.org/). J.L.V. Maag and O.M. Fisher share first authorship and contributed to this article. M.E. Dinger and R.V. Lord share senior authorship of this article

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Conclusion