Transcriptomic profiling reveals three molecular phenotypes of adenocarcinoma at the gastroesophageal junction.
Jan BornscheinLorenz WernischMaria SecrierAhmad MiremadiJuliane PernerShona MacRaeMaria O'DonovanRichard NewtonSuraj MenonLawrence BowerMatthew D EldridgeGinny DevonshireCalvin CheahRichard TurkingtonRichard H HardwickMichael SelgradMarino VeneritoPeter Malfertheinernull nullRebecca C FitzgeraldPublished in: International journal of cancer (2019)
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.
Keyphrases
- single cell
- gene expression
- rna seq
- genome wide
- immune response
- dna methylation
- machine learning
- end stage renal disease
- squamous cell
- electronic health record
- newly diagnosed
- single molecule
- squamous cell carcinoma
- ejection fraction
- big data
- chronic kidney disease
- randomized controlled trial
- open label
- peritoneal dialysis
- mesenchymal stem cells
- radiation therapy
- postmenopausal women
- genome wide analysis
- bone marrow
- childhood cancer
- smoking cessation
- study protocol
- lymph node metastasis
- rectal cancer