Transcriptomic profiling reveals three molecular phenotypes of adenocarcinoma at the gastroesophageal junction. Issue 12 (17th May 2019)

• Record Type: Journal Article
• Authors: Bornschein, Jan; Wernisch, Lorenz; Secrier, Maria; Miremadi, Ahmad; Perner, Juliane; MacRae, Shona; O'Donovan, Maria; Newton, Richard; Menon, Suraj; Bower, Lawrence; Eldridge, Matthew D.; Devonshire, Ginny; Cheah, Calvin; Turkington, Richard; Hardwick, Richard H.; Selgrad, Michael; Venerito, Marino; Malfertheiner, Peter; Fitzgerald, Rebecca C.
• Other Names: Noorani Ayesha investigator.; Elliott Rachael Fels investigator.; Edwards Paul A.W. investigator.; Grehan Nicola investigator.; Nutzinger Barbara investigator.; Crawte Jason investigator.; Chettouh Hamza investigator.; Contino Gianmarco investigator.; Li Xiaodun investigator.; Gregson Eleanor investigator.; Zeki Sebastian investigator.; de la Rue Rachel investigator.; Malhotra Shalini investigator.; Tavaré Simon investigator.; Lynch Andy G. investigator.; Smith Mike L. investigator.; Davies Jim investigator.; Crichton Charles investigator.; Carroll Nick investigator.; Safranek Peter investigator.; Hindmarsh Andrew investigator.; Sujendran Vijayendran investigator.; Hayes Stephen J. investigator.; Ang Yeng investigator.; Preston Shaun R. investigator.; Oakes Sarah investigator.; Bagwan Izhar investigator.; Save Vicki investigator.; Skipworth Richard J.E. investigator.; Hupp Ted R. investigator.; Robert O'Neill J. investigator.; Tucker Olga investigator.; Beggs Andrew investigator.; Taniere Philippe investigator.; Puig Sonia investigator.; Underwood Timothy J. investigator.; Noble Fergus investigator.; Owsley Jack investigator.; Barr Hugh investigator.; Shepherd Neil investigator.; Old Oliver investigator.; Lagergren Jesper investigator.; Gossage James investigator.; Davies Andrew investigator.; Chang Fuju investigator.; Zylstra Janine investigator.; Goh Vicky investigator.; Ciccarelli Francesca D. investigator.; Sanders Grant investigator.; Berrisford Richard investigator.; Harden Catherine investigator.; Bunting David investigator.; Lewis Mike investigator.; Cheong Ed investigator.; Kumar Bhaskar investigator.; Parsons Simon L. investigator.; Soomro Irshad investigator.; Kaye Philip investigator.; Saunders John investigator.; Lovat Laurence investigator.; Haidry Rehan investigator.; Eneh Victor investigator.; Igali Laszlo investigator.; Scott Michael investigator.; Sothi Shamila investigator.; Suortamo Sari investigator.; Lishman Suzy investigator.; Hanna George B. investigator.; Peters Christopher J. investigator.; Grabowska Anna investigator.;
• Is Part Of: International journal of cancer. Volume 145:Issue 12(2019)
• Page Start: 3389
• Page End: 3401
• Publication Date: 2019-05-17
• Subjects: gastric cancer -- esophageal adenocarcinoma -- gastroesophageal junction -- gene expression profiling -- Siewert classification; Cancer -- Periodicals; Cancer -- Prevention -- Periodicals; 616.994
• DOI: 10.1002/ijc.32384
• Languages: English
• ISSNs: 0020-7136

Abstract

Abstract : Cancers occurring at the gastroesophageal junction (GEJ) are classified as predominantly esophageal or gastric, which is often difficult to decipher. We hypothesized that the transcriptomic profile might reveal molecular subgroups which could help to define the tumor origin and behavior beyond anatomical location. The gene expression profiles of 107 treatment‐naïve, intestinal type, gastroesophageal adenocarcinomas were assessed by the Illumina‐HTv4.0 beadchip. Differential gene expression (limma), unsupervised subgroup assignment (mclust) and pathway analysis (gage) were undertaken in R statistical computing and results were related to demographic and clinical parameters. Unsupervised assignment of the gene expression profiles revealed three distinct molecular subgroups, which were not associated with anatomical location, tumor stage or grade ( p > 0.05). Group 1 was enriched for pathways involved in cell turnover, Group 2 was enriched for metabolic processes and Group 3 for immune‐response pathways. Patients in group 1 showed the worst overall survival ( p = 0.019). Key genes for the three subtypes were confirmed by immunohistochemistry. The newly defined intrinsic subtypes were analyzed in four independent datasets of gastric and esophageal adenocarcinomas with transcriptomic data available (RNAseq data: OCCAMS cohort, n = 158; gene expression arrays: Belfast, n = 63; Singapore, n = 191; Asian Cancer Research Group, n = 300). The subgroups were represented in the independent cohorts and pooled analysis confirmed the prognostic effect of the new subtypes. In conclusion, adenocarcinomas at the GEJ comprise three distinct molecular phenotypes which do not reflect anatomical location but rather inform our understanding of the key pathways expressed. Abstract : What's new? Adenocarcinomas that arise at the junction between the esophagus and the stomach are currently classified based on location. Here, the authors looked at patterns of gene expression of these cancers. They found that gastro‐esophageal junction adenocarcinomas can be sorted into three biological subtypes, independent of location, based on gene expression. Group 1 cancers have boosted stomach‐specific genes that combat the effects of acid reflux. Group 2 tumors express genes characteristic to the intestinal tract, and the genes active in Group 3 relate to inflammation. The differences in biological pathway expression means that these differences could be used to improve treatment.