Journal Article

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

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

2012

Overview

ObjectiveGastric 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.DesignUsing 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.Results22 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.ConclusionThe 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.

• Publisher: BMJ Publishing Group Ltd and British Society of Gastroenterology,BMJ Publishing Group,BMJ Publishing Group LTD,BMJ Group
• Subject: Antineoplastic Agents - therapeutic use / Barrett's carcinoma / Barrett's metaplasia / Biological and medical sciences / Breast cancer / cancer / Cancer therapies / cell signalling / Chemotherapy / Clinical trials / colorectal cancer screening / copy number alterations / Gastric cancer / gastric carcinoma / gastric pre-cancer / Gastroenterology. Liver. Pancreas. Abdomen / gastrointesinal endoscopy / gastrointestinal cancer / gastroscopy / Gene Amplification / Gene Deletion / gene expression / gene mutation / Genetic Markers / Medical prognosis / Medical sciences / molecular pathology / Molecular Targeted Therapy / Mortality / Mutation / oesophageal cancer / Oligonucleotide Array Sequence Analysis / Patients / Polymorphism, Single Nucleotide / Proportional Hazards Models / Proteins / Proto-Oncogene Proteins - genetics / Proto-Oncogene Proteins c-met - genetics / Proto-Oncogene Proteins p21(ras) / ras Proteins - genetics / receptor tyrosine kinases / Receptor, Epidermal Growth Factor - genetics / Receptor, ErbB-2 - genetics / Receptor, Fibroblast Growth Factor, Type 2 - genetics / Stomach / Stomach Neoplasms - drug therapy / Stomach Neoplasms - genetics / Stomach Neoplasms - mortality / Stomach. Duodenum. Small intestine. Colon. Rectum. Anus / Studies / targeted therapies / Tumors