A comprehensive survey of genomic alterations in gastric cancer reveals systematic patterns of molecular exclusivity and co-occurrence among distinct therapeutic targets. Issue 5 (7th February 2012)

• Record Type: Journal Article
• Authors: Deng, Niantao; Goh, Liang Kee; Wang, Hannah; Das, Kakoli; Tao, Jiong; Tan, Iain Beehuat; Zhang, Shenli; Lee, Minghui; Wu, Jeanie; Lim, Kiat Hon; Lei, Zhengdeng; Goh, Glenn; Lim, Qing-Yan; Tan, Angie Lay-Keng; Sin Poh, Dianne Yu; Riahi, Sudep; Bell, Sandra; Shi, Michael M; Linnartz, Ronald; Zhu, Feng; Yeoh, Khay Guan; Toh, Han Chong; Yong, Wei Peng; Cheong, Hyun Cheol; Rha, Sun Young; Boussioutas, Alex; Grabsch, Heike; Rozen, Steve; Tan, Patrick
• Is Part Of: Gut. Volume 61:Issue 5(2012)
• Page Start: 673
• Page End: 684
• Publication Date: 2012-02-07
• Subjects: Barrett's carcinoma -- Barrett's metaplasia -- cancer -- cell signalling -- chemotherapy -- colorectal cancer screening -- copy number alterations -- gastric cancer -- gastric carcinoma -- gastric pre-cancer -- gastrointestinal cancer -- gastrointesinal endoscopy -- gastroscopy -- gene expression -- gene mutation -- molecular pathology -- oesophageal cancer -- receptor tyrosine kinases -- targeted therapies; Gastroenterology -- Periodicals; 616.33
• DOI: 10.1136/gutjnl-2011-301839
• Languages: English
• ISSNs: 0017-5749

Abstract

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.