Comprehensive genomic meta-analysis identifies intra-tumoural stroma as a predictor of survival in patients with gastric cancer

Yonghui Wu, Heike Grabsch, Tatiana Ivanova, Iain Beehuat Tan, Jacinta Murray, Chia Huey Ooi, Alexander Ian Wright, Nicholas P. West, Gordon G.A. Hutchins, Jeanie Wu, Minghui Lee, Julian Lee, Jun Hao Koo, Khay Guan Yeoh, Nicole Van Grieken, Bauke Ylstra, Sun Young Rha, Jaffer A. Ajani, Jae Ho Cheong, Sung Hoon NohKiat Hon Lim, Alex Boussioutas, Ju Seog Lee, Patrick Tan

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Abstract

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 nonmalignant 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.

Original languageEnglish
Pages (from-to)1100-1111
Number of pages12
JournalGut
Volume62
Issue number8
DOIs
Publication statusPublished - 2013 Aug 1

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All Science Journal Classification (ASJC) codes

  • Gastroenterology

Cite this

Wu, Y., Grabsch, H., Ivanova, T., Tan, I. B., Murray, J., Ooi, C. H., Wright, A. I., West, N. P., Hutchins, G. G. A., Wu, J., Lee, M., Lee, J., Koo, J. H., Yeoh, K. G., Van Grieken, N., Ylstra, B., Rha, S. Y., Ajani, J. A., Cheong, J. H., ... Tan, P. (2013). Comprehensive genomic meta-analysis identifies intra-tumoural stroma as a predictor of survival in patients with gastric cancer. Gut, 62(8), 1100-1111. https://doi.org/10.1136/gutjnl-2011-301373