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.
Highlights
Incidence of tumors at the gastroesophageal junction (GEJ) has increased rapidly over the past 50 years.[1]
There was no significant difference in clinical parameters between the Siewert types, apart from an expected higher proportion of Barrett’s esophagus in patients with GEJ1 cancers
Differential gene expression analysis between tumors of different Siewert types using limma[19] revealed that REC8 (REC8 Meiotic Recombination Protein) was the only gene with differential expression when comparing between GEJ1 and GEJ3 tumors (FDR: p = 0.004), and SESN1 (Sestrin-1) between GEJ2 and GEJ3 tumors (FDR: p = 0.024)
Summary
Incidence of tumors at the gastroesophageal junction (GEJ) has increased rapidly over the past 50 years.[1]. With newly emerging systemic treatment options and multimodal therapy concepts being more dominant in curative treatment approaches, understanding of the biological processes that define different tumor subtypes is becoming increasingly important. Cancers in the distal part of the GEJ (Siewert Type 3) are more likely to arise from the proximal stomach.[3,4,5,6,7] Proximal GEJ tumors (Siewert Type 1), on the other hand, are most likely of esophageal origin.[5] It remains not clear if tumors originating directly from the GEJ (Siewert Type 2) comprise a mixed group of esophageal or gastric cancers or if these constitute a separate entity with distinct biological behavior. Previous molecular classifications were mainly based on the genomic features which do not necessarily reflect the active gene transcription landscape
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