A comprehensive survey of genomic alterations in gastric cancer reveals systematic patterns of molecular exclusivity and co-occurrence among distinct therapeutic targets
- Niantao Deng1,2,
- Liang Kee Goh1,3,4,
- Hannah Wang1,
- Kakoli Das1,
- Jiong Tao1,5,
- Iain Beehuat Tan1,2,4,
- Shenli Zhang1,
- Minghui Lee6,
- Jeanie Wu6,
- Kiat Hon Lim7,
- Zhengdeng Lei8,
- Glenn Goh1,
- Qing-Yan Lim9,
- Angie Lay-Keng Tan1,
- Dianne Yu Sin Poh1,
- Sudep Riahi10,
- Sandra Bell10,
- Michael M Shi11,
- Ronald Linnartz11,
- Feng Zhu12,
- Khay Guan Yeoh12,
- Han Chong Toh4,
- Wei Peng Yong13,
- Hyun Cheol Cheong14,
- Sun Young Rha14,
- Alex Boussioutas15,
- Heike Grabsch16,
- Steve Rozen8,
- Patrick Tan1,6,17,18
- 1Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School, Singapore
- 2NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore
- 3Saw Swee Hock School of Public Health, National University of Singapore, Singapore
- 4Division of Medical Oncology, National Cancer Centre, Singapore
- 5Department of Physiology, National University of Singapore, Singapore
- 6Cellular and Molecular Research, National Cancer Centre, Singapore
- 7Department of Pathology, Singapore General Hospital, Singapore
- 8Neuroscience and Behavioral Disorders, Duke-NUS Graduate Medical School, Singapore
- 9School of Biological Sciences, Nanyang Technological University, Singapore
- 10Section of Ophthalmology and Neuroscience, Leeds Institute for Molecular Medicine, Leeds, UK
- 11Novartis Oncology, East Hanover, New Jersey, USA
- 12Department of Medicine, National University Health System, Singapore
- 13National Cancer Institute Singapore, National University Health System, Singapore
- 14Department of Internal Medicine, Yonsei Cancer Centre, Yonsei, South Korea
- 15Cancer Genomics and Biochemistry Laboratory, Peter MacCallum Cancer Centre, Melbourne, Australia
- 16Department of Pathology and Tumour Biology, Leeds Institute for Molecular Medicine, Leeds, UK
- 17Cancer Science Institute of Singapore, National University of Singapore, Singapore
- 18Genome Institute of Singapore, Singapore
- Correspondence to Dr Patrick Tan, Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School, 8 College Road, Singapore 169857, Singapore;
Contributors ND, LKG and PT wrote the paper. ND, LKG, HW, KD, JT, SZ, IBT, ZL, GG, HG and PT analysed the data. HW, KD, JT, SZ, ML, JW, GG, QYL, ALKT, DYSP and SR conducted the experiments. KHL, MMS, RL, FZ, KGY, HCT, WPY, HCC, SYR and AB contributed data and reagents. LKG, SB, HG, SR and PT supervised the research. The first two authors contributed equally to this study.
- Revised 9 January 2012
- Accepted 10 January 2012
- Published Online First 7 February 2012
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.
- Barrett's carcinoma
- Barrett's metaplasia
- cell signalling
- colorectal cancer screening
- copy number alterations
- gastric cancer
- gastric carcinoma
- gastric pre-cancer
- gastrointestinal cancer
- gastrointesinal endoscopy
- gene expression
- gene mutation
- molecular pathology
- oesophageal cancer
- receptor tyrosine kinases
- targeted therapies
See Commentary, p 638
Accession number in NCBI GEO database: GSE31168.
Funding This study was supported by NMRC grants TCR/001/2007, BMRC 10/1/24/19/655, BMRC-NMRC 10/1/33/19/676 and core grants from Duke-National University of Singapore and the Cancer Sciences Institute of Singapore to PT. This work was also supported by an ASCO grant to IBT, a Singhealth talent development grant to IBT and Priscilla Ng and a Khoo discovery award (KDP/2008/0002 and KDP/2009/0006) to LKG.
Competing interests MMS and RL are employees of Novartis Pharmaceuticals Corporation. All other authors declare that they have no competing interests.
Patient consent Obtained.
Ethics approval Ethics approval was provided by the Institutional Research Ethics Review Committees of Singapore Health Services and the National University Hospital System.
Provenance and peer review Not commissioned; externally peer reviewed.
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