A comprehensive survey of genomic alterations in gastric cancer reveals systematic patterns of molecular exclusivity and co-occurrence among distinct therapeutic targets

Niantao Deng, Liang Kee Goh, Hannah Wang, Kakoli Das, Jiong Tao, Iain Beehuat Tan, Shenli Zhang, Minghui Lee, Jeanie Wu, Kiat Hon Lim, Zhengdeng Lei, Glenn Goh, Qing Yan Lim, Angie Lay Keng Tan, Dianne Yu Sin Poh, Sudep Riahi, Sandra Bell, Michael M. Shi, Ronald Linnartz, Feng ZhuKhay Guan Yeoh, Han Chong Toh, Wei Peng Yong, Hyun Cheol Cheong, Sun Young Rha, Alex Boussioutas, Heike Grabsch, Steve Rozen, Patrick Tan

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410 Citations (Scopus)

Abstract

Objective: Gastric cancer is a major gastrointestinal malignancy for which targeted therapies are emerging as treatment options. This study sought to identify the most prevalent molecular targets in gastric cancer and to elucidate systematic patterns of exclusivity and co-occurrence among these targets, through comprehensive genomic analysis of a large panel of gastric cancers. Design: Using high-resolution single nucleotide polymorphism arrays, copy number alterations were profiled in a panel of 233 gastric cancers (193 primary tumours, 40 cell lines) and 98 primary matched gastric non-malignant samples. For selected alterations, their impact on gene expression and clinical outcome were evaluated. Results: 22 recurrent focal alterations (13 amplifications and nine deletions) were identified. These included both known targets (FGFR2, ERBB2) and also novel genes in gastric cancer (KLF5, GATA6). Receptor tyrosine kinase (RTK)/RAS alterations were found to be frequent in gastric cancer. This study also demonstrates, for the first time, that these alterations occur in a mutually exclusive fashion, with KRAS gene amplifications highlighting a clinically relevant but previously underappreciated gastric cancer subgroup. FGFR2-amplified gastric cancers were also shown to be sensitive to dovitinib, an orally bioavailable FGFR/VEGFR targeting agent, potentially representing a subtype-specific therapy for FGFR2-amplified gastric cancers. Conclusion: The study demonstrates the existence of five distinct gastric cancer patient subgroups, defined by the signature genomic alterations FGFR2 (9% of tumours), KRAS (9%), EGFR (8%), ERBB2 (7%) and MET (4%). Collectively, these subgroups suggest that at least 37% of gastric cancer patients may be potentially treatable by RTK/RAS directed therapies.

Original languageEnglish
Pages (from-to)673-684
Number of pages12
JournalGut
Volume61
Issue number5
DOIs
Publication statusPublished - 2012 May

All Science Journal Classification (ASJC) codes

  • Gastroenterology

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    Deng, N., Goh, L. K., Wang, H., Das, K., Tao, J., Tan, I. B., Zhang, S., Lee, M., Wu, J., Lim, K. H., Lei, Z., Goh, G., Lim, Q. Y., Tan, A. L. K., Poh, D. Y. S., Riahi, S., Bell, S., Shi, M. M., Linnartz, R., ... Tan, P. (2012). A comprehensive survey of genomic alterations in gastric cancer reveals systematic patterns of molecular exclusivity and co-occurrence among distinct therapeutic targets. Gut, 61(5), 673-684. https://doi.org/10.1136/gutjnl-2011-301839