Objective Gastric adenocarcinoma (gastric cancer, GC) is a major cause of global cancer mortality. Identifying molecular programmes contributing to GC patient survival may improve our understanding of GC pathogenesis, highlight new prognostic factors and reveal novel therapeutic targets. The authors aimed to produce a comprehensive inventory of gene expression programmes expressed in primary GCs, and to identify those expression programmes significantly associated with patient survival.
Design Using a network-modelling approach, the authors performed a large-scale meta-analysis of GC transcriptome data integrating 940 gastric transcriptomes from multiple independent patient cohorts. The authors analysed a training set of 428 GCs and 163 non-malignant gastric samples, and a validation set of 288 GCs and 61 non-malignant gastric samples.
Results The authors identified 178 gene expression programmes (‘modules’) expressed in primary GCs, which were associated with distinct biological processes, chromosomal location patterns, cis-regulatory motifs and clinicopathological parameters. Expression of a transforming growth factor β (TGF-β) signalling associated ‘super-module’ of stroma-related genes consistently predicted patient survival in multiple GC validation cohorts. The proportion of intra-tumoural stroma, quantified by morphometry in tissue sections from gastrectomy specimens, was also significantly associated with stromal super-module expression and GC patient survival.
Conclusion Stromal gene expression predicts GC patient survival in multiple independent cohorts, and may be closely related to the intra-tumoural stroma proportion, a specific morphological GC phenotype. These findings suggest that therapeutic approaches targeting the GC stroma may merit evaluation.
Wu Y1*, Grabsch H2 *, Ivanova T1, Tan IB, Murray J2 , Ooi CH4 , Wright AI2 , West NP2 , Hutchins GG2 , Wu J1, Lee M1, Lee J1, Koo JH1, Yeoh KG5, van Grieken N6, Ylstra B6, Rha SY7, Ajani JA8, Cheong JH9, Noh SH9, Lim KH10, Boussioutas A11,12 , Lee JS13 , Tan P4, 14 ,15 .
*These authors contributed equally to this work.
1Cellular and Molecular Research, National Cancer Centre, Singapore
2Pathology and Tumour Biology, Leeds Institute of Molecular Medicine, University of Leeds, UK
3Division of Medical Oncology, National Cancer Centre, Singapore
4Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, Singapore
5Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore
6Department of Pathology, Free University Medical Center Amsterdam, The Netherlands
7Department of Internal Medicine, Yonsei Cancer Centre, South Korea
8Departments of Gastrointestinal Medical Oncology, MD Anderson Cancer Centre, USA
9Department of Surgery, Yonsei University College of Medicine, South Korea
10Department of Pathology, Singapore General Hospital, Singapore
11Cancer Genomics and Biochemistry Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia
12Department of Medicine (RMH/WH), University of Melbourne, Western Hospital, Footscray, Victoria, Australia
13Systems Biology, Division of Cancer Medicine, MD Anderson Cancer Centre, USA
14Cancer Science Institute of Singapore, Yong Loo Lin School of Medicine, National University of Singapore
15Genome Institute of Singapore, Singapore