Heterogeneity in gastric cancer and the impact on patient survival

Abstract

Gastric cancer (GC) is one of the most common malignancies and is frequently fatal. Epidemiological and biological evidence suggests GC is heterogeneous, with four subtypes of GC identified by the Cancer Genome Atlas (TCGA) in 2014, however currently it is treated as one disease. The aim of this thesis is to investigate how the clinical and biological inter-tumoural heterogeneity of GC affects survival.

The clinical predictors of outcome were investigated for a cohort of curatively treated GC patients, revealing that age, stage of disease and Lauren histological subtype predict overall, cancer specific and relapse free survival. The molecular differences between different GC stages, and histological subtype (intestinal gastric cancer (IGC) compared to diffuse gastric cancer (DGC)) were then investigated with the aim of understanding the biological basis underlying survival, relapse and response to treatment. Key molecular pathways were identified as being differentially expressed between DGC and IGC, and having impact on survival. These included the transforming growth factor beta (TGF-β) signalling pathway with the expression of three bone morphogenic protein (BMP) antagonists from this pathway having associations with survival on multivariate analysis, and the mismatch repair (MMR) pathway with four genes from this pathway having impact on survival.

BMP and activin membrane bound inhibitor (BAMBI), a gene from the TGF-β pathway was more highly expressed in IGC compared to DGC and was associated with poorer survival in IGC. Molecular analysis of BAMBI in GC cell lines revealed decreased proliferation and invasion, and G0/G1 cell cycle arrest. It was postulated that this change in proliferation and invasion was mediated via alterations in the balance of epithelial-to-mesenchymal transition (EMT) and mesenchymal-to-epithelial transition via a TGF-β mediated process. Further analysis revealed gene expression correlation between BMP antagonists and EMT associated genes, revealing highest correlation with gremlin 1 (GREM1). Higher expression of GREM1 was also associated with poorer survival in IGC.

Another key pathway discovered as differentially expressed between DGC and IGC was the MMR pathway. Microsatellite instability was also identified as a molecular subtype of GC by the TCGA. The clinical and histological correlations of the MMR GC subtype were therefore examined. Patients with MMR deficient tumours had improved survival compared to MMR stable tumours, and a higher inflammatory score (IS). The simple IS used in this thesis could be a triaging tool to identify tumours to take forward for formal MMR testing.

This thesis adds to the growing body of evidence that demonstrates GC is heterogeneous and elaborates on some of the molecular features that drive this inter-tumour heterogeneity. It identifies a number of genes, pathways and biological associations that impact survival, and potentially response to treatment. This work will help in the personalisation of medical therapy for a disease that can no longer be treated with a one-size-fits-all mentality for therapy. Future work is planned to expand the findings of this work, with the aim of translating these findings to the clinical setting, enabling better prognostication and more rational prescription of treatments for GC patients.