Comprehensive genomic meta-analysis identifies intra-tumoural stroma as a predictor of survival in patients with gastric cancer
- Yonghui Wu1,
- Heike Grabsch2,
- Tatiana Ivanova1,
- Iain Beehuat Tan3,
- Jacinta Murray2,
- Chia Huey Ooi4,
- Alexander Ian Wright2,
- Nicholas P West2,
- Gordon G A Hutchins2,
- Jeanie Wu1,
- Minghui Lee1,
- Julian Lee1,
- Jun Hao Koo1,
- Khay Guan Yeoh5,
- Nicole van Grieken6,
- Bauke Ylstra6,
- Sun Young Rha7,
- Jaffer A Ajani8,
- Jae Ho Cheong9,
- Sung Hoon Noh9,
- Kiat Hon Lim10,
- Alex Boussioutas11,12,
- Ju-Seog Lee13,
- Patrick Tan4,14,15
- 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
- Correspondence to Dr Patrick Tan, Associate Professor, Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School Singapore, 8 College Road, Singapore, 169857;
Contributors YW and HG contributed equally to this work. YW, HG and PT conceived and designed the experiments. HG, TI, JM AW, LKH, WN and HG performed the experiments. YW, CHO, JL and HG analysed the data. HG, IBT, JW, ML, JHK, KGY, NvG, BY, SYR, JAA, JHC, SHN, LKH, AB and J-SL contributed reagents/materials/analysis tools. YW, HG and PT wrote the paper.
- Revised 8 May 2012
- Accepted 15 May 2012
- Published Online First 26 June 2012
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.
- Gastric cancer
- gene expression
- prognostic factors
- oesophageal cancer
- molecular pathology
- gastric adenocarcinoma
- colorectal cancer
- image analysis
- Helicobacter pylori–gastritis
- Barrett's metaplasia
- Barrett's carcinoma
- colorectal cancer screening
- gastric pre-cancer
Funding This work was supported by Grants to PT from the Biomedical Research Council of Singapore (Grant 05/1/31/19/423), the National Medical Research Council of Singapore (Grant TCR/001/2007), and internal grants from the Duke-National University of Singapore Graduate Medical School, and the Cancer Sciences Institute of Singapore. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.
Competing interests None.
Patient consent Obtained.
Ethics approval Primary gastric cancer tissue samples were collected with patient consent from the participating centre's tissue repositories or pathology archives and approval by the respective institutional Research Ethics Review Committees in accordance with local regulations and legislations. Clinical information was collected with Institutional Review Board approval.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement The microarray data in this study is available from GEO under accession numbers GSE2669, GSE2680, GSE2685, GSE2637, GSE3438, GSE15459, GSE13861, GSE37023, GSE35809 and http://smd.stanford.edu/cgi-bin/publication/viewPublication.pl?pub_no=516.