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

Abstract

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.

Semi-comprehensive analysis of gene amplification in gastric cancers using multiplex ligation-dependent probe amplification and fluorescence in situ hybridization

“…This characteristic of RTKs is one of the reasons why RTK gene amplifications have attracted much attention as molecular targets even though the prevalence of individual RTK gene amplification is low. 6,12,13 However, if small fractions of amplified cells that cannot be detect by screening with multiplex ligation-dependent probe amplification and/or early gastric cancers are included, co-amplification of RTK genes is not exceptional in gastric cancers. On the contrary, our previous study showed a marginal trend for co-amplification of EGFR and ERBB2; however, this trend was not statistically significant.…”

“…As for RTK genes, the hypothesis that 'amplification causes overexpression' is fundamentally established for ERBB2, and is highly supported for EGFR, FGFR2, and MET. [10][11][12][13][14] However, even for RTKs, inconsistent results between FISH and immunohistochemical analyses were often obtained, mostly because of inherent technical reasons of immunohistochemistry such as specificity of antibodies, fixative used, duration of fixation, staining procedures, and/or scoring system. Therefore, at the present time gene amplification provides the best biomarkers for helping to select the right patient candidate for molecular therapy targeted toward these genes, and multiplex ligation-dependent probe amplification is the most feasible method for screening these gene amplifications.…”

“…8,9 In preclinical studies, cells with amplified FGFR2 or MET showed overexpression of their respective proteins, and inhibitors to these receptors were shown to effectively block their downstream signal transduction and induce apoptosis. [10][11][12][13][14] At present, apart from ERBB2 targeting, approaches for targeting MET and FGFR2 are the most clinically advanced of prospective targeted therapy. However, the prevalence of amplification of each of these genes, as assessed by oligonucleotide array comparative genetic hybridization, real-time PCR, fluorescence in situ hybridization (FISH), or silver in situ hybridization is low, ie, from 2 to 5% for FGFR2, 9,10,12,14 and from 2 to 8% for MET, respectively.…”

“…However, the prevalence of amplification of each of these genes, as assessed by oligonucleotide array comparative genetic hybridization, real-time PCR, fluorescence in situ hybridization (FISH), or silver in situ hybridization is low, ie, from 2 to 5% for FGFR2, 9,10,12,14 and from 2 to 8% for MET, respectively. 6,7,14,15 Intriguingly, a recent comprehensive genome-wide analysis of copy number alterations using an single nucleotide polymorphism array 13 showed that amplification of FGFR2, EGFR, ERBB2, and MET occurred mutually exclusively and that other genes such as MYC and CCND1 were also amplified in gastric cancer. When considering promising targets of molecular therapy, the apparently low prevalence of these gene amplifications in gastric cancer makes selection of the right set of patients that can benefit from targeted therapy a difficult challenge.…”

FGFR2 in gastric cancer: protein overexpression predicts gene amplification and high H-index predicts poor survival

“…11 In previous studies, the frequency of FGFR2 amplification varied from 3 to 9% depending on the testing methods. 4,5,[12][13][14][15][16][17][18] The prevalence rates also varied between countries-7% in the United Kingdom, 5% in China, and 4% in Korea-using the same FISH test analyzed in one core laboratory. 18 Nevertheless, the frequency of FGFR2 overexpression detection by immunohistochemistry ranged from 31% up to 51%-which were considerably higher than the incidence of FGFR2 amplifica tions.…”