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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.

Barrett's esophagus (BE), a common condition, is the only known precursor to esophageal adenocarcinoma (EAC). There is uncertainty about the best way to manage BE as most people with BE never develop EAC and most patients diagnosed with EAC have no preceding diagnosis of BE. Moreover, there have been recent advances in knowledge and practice about the management of BE and early EAC. To aid clinical decision making in this rapidly moving field, Cancer Council Australia convened an expert working party to identify pertinent clinical questions. The questions covered a wide range of topics including endoscopic and histological definitions of BE and early EAC; prevalence, incidence, natural history, and risk factors for BE; and methods for managing BE and early EAC. The latter considered modification of lifestyle factors; screening and surveillance strategies; and medical, endoscopic, and surgical interventions. To answer each question, the working party systematically reviewed the literature and developed a set of recommendations through consensus. Evidence underpinning each recommendation was rated according to quality and applicability.

Background Cathepsin E (CTSE), an aspartic proteinase, is differentially expressed in the metaplasia–dysplasia–neoplasia sequence of gastric and colon cancer. We evaluated CTSE in Barrett’s esophagus (BE) and cancer because increased CTSE levels are linked to improved survival in several cancers, and other cathepsins are up-regulated in BE and esophageal adenocarcinoma (EAC). Methods A total of 273 pretreatment tissues from 199 patients were analyzed [31 normal squamous esophagus (NE), 29 BE intestinal metaplasia, 31 BE with dysplasia (BE/D), 108 EAC]. CTSE relative mRNA expression was measured by real-time polymerase chain reaction, and protein expression was measured by immunohistochemistry. CTSE serum levels were determined by enzyme-linked immunosorbent assay. Results Median CTSE mRNA expression levels were ≥1,000-fold higher in BE/intestinal metaplasia and BE/D compared to NE. CTSE levels were significantly lower in EAC compared to BE/intestinal metaplasia and BE/D, but significantly higher than NE levels. A similar expression pattern was present in immunohistochemistry, with absent staining in NE, intense staining in intestinal metaplasia and dysplasia, and less intense EAC staining. CTSE serum analysis did not discriminate patient groups. In a uni- and multivariable Cox proportional hazards model, CTSE expression was not significantly associated with survival in patients with EAC, although CTSE expression above the 25th percentile was associated with a 41 % relative risk reduction for death (hazard ratio 0.59, 95 % confidence interval 0.27–1.26, p = 0.17). Conclusions CTSE mRNA expression is up-regulated more than any known gene in Barrett intestinal metaplasia and dysplasia tissues. Protein expression is similarly highly intense in intestinal metaplasia and dysplasia tissues. Electronic supplementary material The online version of this article (doi:10.1245/s10434-014-4155-y) contains supplementary material, which is available to authorized users.

Background: Endoscopic treatment by either radiofrequency (RFA) ablation or endoscopic mucosal resection (EMR) has become first line treatment for Barrett's esophagus (BE) with high grade dysplasia, while focal EMR and subsequent elimination of the residual segment by RFA or EMR is accepted therapy for intramucosal cancer (IMC). RFA and EMR are known to be clinically effective but the effect on the mRNA expression of molecular markers of disease stage, which may inform the long term risk of progression to adenocarcinoma, is unknown. We compared the mRNA expression profile in pre-treatment BE tissues biopsies and post-treatment neo-squamous tissues from the same level to provide a surrogatemolecular estimate of treatment effect. Methods: Paired pre-treatment BE tissues and post-treatment neosquamous biopsies were obtained from 38 patients treated by RFA (20 patients (3 IMC (prior EMR), 5 HGD, 12 LGD) or EMR (18 patients, 6 IMC, 12 HGD). mRNA expression of 16 genes significantly associated with different BE stages was measured using a multiplex tandem RT-PCR method with preand post-treatment tissues assessed simultaneously. Distal esophageal tissues from 12 patients with no history of GERD or BE were used as normal controls. Results: Endoscopic therapy resulted in a highly significant change in median values towards the normal squamous mucosa expression profile for all 16 genes on unpaired analysis. This change remained significant for 12 genes by paired analysis (t test). The only significant treatment differences in pre-post mean difference in gene expression were greater changes for RFA compared to EMR for 5 genes. The neosquamous expression profile was significantly different to the normal control profile for 9 of 16 genes. Conclusions: Both RFA and EMR result in marked changes in mRNA expression, with replacement of the highly disordered Barrett's dysplasia or IMC expression profile with a more "normal" expression profile. The neosquamous mucosa was significantly different to the normal control squamous mucosa for most genes but the significance of this finding is uncertain and may reflect confounding factors.