Transcriptomic profiling reveals three molecular phenotypes of adenocarcinoma at the gastro‐esophageal junction
Authors listJan Bornschein Lorenz Wernisch Maria Secrier Ahmad Miremadi Juliane Perner Shona MacRae Maria O'Donovan Richard Newton Suraj Menon Lawrence Bower Matthew D Eldridge Ginny Devonshire Calvin Cheah Richard Turkington Richard H Hardwick Michael Selgrad Marino Venerito Peter Malfertheiner Rebecca C Fitzgerald Ayesha Noorani Rachael Fels Elliott Paul AW Edwards Nicola Grehan Barbara Nutzinger Jason Crawte Hamza Chettouh Gianmarco Contino Xiaodun Li Eleanor Gregson Sebastian Zeki Rachel Rue Shalini Malhotra Simon Tavaré Andy G Lynch Mike L Smith Jim Davies Charles Crichton Nick Carroll Peter Safranek Andrew Hindmarsh Vijayendran Sujendran Stephen J Hayes Yeng Ang Shaun R Preston Sarah Oakes Izhar Bagwan Vicki Save Richard JE Skipworth Ted R Hupp J Robert O'Neill Olga Tucker Andrew Beggs Philippe Taniere Sonia Puig Timothy J Underwood Fergus Noble Jack Owsley Hugh Barr Neil Shepherd Oliver Old Jesper Lagergren James Gossage Andrew Davies Fuju Chang Janine Zylstra Vicky Goh Francesca Ciccarelli Grant Sanders Richard Berrisford Catherine Harden David Bunting Mike Lewis Ed Cheong Bhaskar Kumar Simon L Parsons Irshad Soomro Philip Kaye John Saunders Laurence Lovat Rehan Haidry Victor Eneh Laszlo Igali Michael Scott Shamila Sothi Sari Suortamo Suzy Lishman George B Hanna Christopher J Peters Anna Grabowska OCCAMS Consortium
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.