Diffuse-type gastric carcinoma (DGC) is an aggressive subtype of gastric carcinoma with an extremely poor prognosis due to frequent peritoneal metastasis and high probability of recurrence. Its pathogenesis is poorly understood, and consequently, no effective molecular targeted therapy is available. The importance of oncogenic receptor tyrosine kinase (RTK) signaling has been recently demonstrated in the malignant progression of DGC. In particular, RTK gene amplification appears to accelerate peritoneal metastasis. In this review, we provide an overview of RTK gene amplification in DGC and the potential of related targeted therapies.

Gastric cancer (GC) is a major cause of cancer-related death worldwide. Patients with an aggressive subtype of GC, known as diffuse-type gastric carcinoma (DGC), have extremely poor prognoses. DGC is characterized by rapid infiltrative growth, massive desmoplastic stroma, frequent peritoneal metastasis, and high probability of recurrence. These clinical features and progression patterns of DGC substantially differ from those of other GC subtypes, suggesting the existence of specific oncogenic signals. The importance of gene amplification and the resulting aberrant activation of receptor tyrosine kinase (RTK) signaling in the malignant progression of DGC is becoming apparent. Here, we review the characteristics of RTK gene amplification in DGC and its importance in peritoneal metastasis. These insights may potentially lead to new targeted therapeutics.

Bemarituzumab (FPA144) is a first-in-class, humanized, afucosylated immunoglobulin G1 monoclonal antibody (mAb) directed against fibroblast growth factor receptor 2b (FGFR2b) with two mechanisms of action against FGFR2b-overexpressing tumors: inhibition of FGFR2b signaling and enhanced antibody-dependent cell-mediated cytotoxicity (ADCC). Bemarituzumab is being developed as a cancer therapeutic, and we summarize here the key nonclinical data that supported moving it into clinical trials. Bemarituzumab displayed sub-nanomolar cross-species affinity for FGFR2b receptors, with >20-fold enhanced binding affinity to human Fc gamma receptor IIIa compared with the fucosylated version. In vitro, bemarituzumab induced potent ADCC against FGFR2b-expressing tumor cells, and inhibited FGFR2 phosphorylation and proliferation of SNU-16 gastric cancer cells in a concentration-dependent manner. In vivo, bemarituzumab inhibited tumor growth through inhibition of the FGFR2b pathway and/or ADCC in mouse models. Bemarituzumab demonstrated enhanced anti-tumor activity in combination with chemotherapy, and due to bemarituzumab-induced natural killer cell-dependent increase in programmed death-ligand 1, also resulted in enhanced anti-tumor activity when combined with an anti-programmed death-1 antibody. Repeat-dose toxicity studies established the highest non-severely-toxic dose at 1 and 100 mg/kg in rats and cynomolgus monkeys, respectively. In pharmacokinetic (PK) studies, bemarituzumab exposure increase was greater than dose-proportional, with the linear clearance in the expected dose range for a mAb. The PK data in cynomolgus monkeys were used to project bemarituzumab linear PK in humans, which were consistent with the observed human Phase 1 data. These key nonclinical studies facilitated the successful advancement of bemarituzumab into the clinic.

• Bemarituzumab
• afucosylated antibody; antibody-dependent cell-mediated cytoxicity; phosphorylation in vitro
• anti-FGFR2b antibody
• anti-tumor efficacy
• cell proliferation in vitro
• fibroblast growth factor receptor
• pharmacokinetics
• toxicology

Diffuse-type gastric carcinoma (DGC) is characterized by rapid infiltrative growth associated with massive stroma and frequent peritoneal dissemination, which leads to poor patient outcomes. In this study, we found that the oncogenic tyrosine phosphatase SHP2 is tyrosine-phosphorylated downstream of the amplified receptor tyrosine kinases (RTKs) Met and fibroblast growth factor receptor 2 (FGFR2) in DGC cell lines. SHP2 knockdown or pharmacological inhibition selectively suppressed the growth of DGC addicted to amplified Met and FGFR2. Moreover, targeting SHP2 abrogated malignant phenotypes, including peritoneal dissemination, of Met-addicted DGC and could overcome acquired resistance to Met inhibitors. Our findings suggest that SHP2 is a potential target for the treatment of DGC addicted to amplified RTK signaling.

Diffuse-type gastric carcinoma (DGC) exhibits aggressive progression associated with rapid infiltrative growth, massive fibrosis, and peritoneal dissemination. Gene amplification of Met and fibroblast growth factor receptor 2 (FGFR2) receptor tyrosine kinases (RTKs) has been observed in DGC. However, the signaling pathways that promote DGC progression downstream of these RTKs remain to be fully elucidated. We previously identified an oncogenic tyrosine phosphatase, SHP2, using phospho-proteomic analysis of DGC cells with Met gene amplification. In this study, we characterized SHP2 in the progression of DGC and assessed the therapeutic potential of targeting SHP2. Although SHP2 was expressed in all gastric carcinoma cell lines examined, its tyrosine phosphorylation preferentially occurred in several DGC cell lines with Met or FGFR2 gene amplification. Met or FGFR inhibitor treatment or knockdown markedly reduced SHP2 tyrosine phosphorylation. Knockdown or pharmacological inhibition of SHP2 selectively suppressed the growth of DGC cells addicted to Met or FGFR2, even when they acquired resistance to Met inhibitors. Moreover, SHP2 knockdown or pharmacological inhibition blocked the migration and invasion of Met-addicted DGC cells in vitro and their peritoneal dissemination in a mouse xenograft model. These results indicate that SHP2 is a critical regulator of the malignant progression of RTK-addicted DGC and may be a therapeutic target.

• Met
• SHP2
• diffuse-type gastric carcinoma
• peritoneal dissemination
• receptor tyrosine kinase

• EGFR
• FGFRs
• FGFs
• cancer
• cell adhesion molecules
• coreceptors
• extracellular matrix
• receptor tyrosine kinase
• signaling
• tumorigenesis

• Carcinogenesis
• Humans
• Neoplasms/metabolism
• Receptor, Fibroblast Growth Factor, Type 1/metabolism
• Receptor, Fibroblast Growth Factor, Type 2/metabolism

• MR/T016043/1 Medical Research Council
• BB/R015864/1 Biotechnology and Biological Sciences Research Council
• 107636/Z/15/Z Wellcome Trust
• BB/M011208/1 Biotechnology and Biological Sciences Research Council

The recent discovery of nuclear and perinuclear perlecan in annulus fibrosus and nucleus pulposus cells and its known matrix stabilizing properties in tissues introduces the possibility that perlecan may also have intracellular stabilizing or regulatory roles through interactions with nuclear envelope or cytoskeletal proteins or roles in nucleosomal-chromatin organization that may regulate transcriptional factors and modulate gene expression. The nucleus is a mechano-sensor organelle, and sophisticated dynamic mechanoresponsive cytoskeletal and nuclear envelope components support and protect the nucleus, allowing it to perceive and respond to mechano-stimulation. This review speculates on the potential roles of perlecan in the nucleus based on what is already known about nuclear heparan sulphate proteoglycans. Perlecan is frequently found in the nuclei of tumour cells; however, its specific role in these diseased tissues is largely unknown. The aim of this review is to highlight probable roles for this intriguing interactive regulatory proteoglycan in the nucleus of normal and malignant cell types.

• glypican
• heparan sulphate
• heparan sulphate proteoglycan
• nucleus
• perlecan
• syndecan
• tensegrity

Met gene amplification has been found in a subset of malignant carcinomas, including diffuse-type gastric carcinoma (DGC), which has a poor prognosis owing to rapid infiltrative invasion and frequent peritoneal dissemination. Met is considered a promising therapeutic target for DGC. However, DGC cells with Met gene amplification eventually acquire resistance to Met inhibitors. Therefore, identification of alternate targets that mediate Met signaling and confer malignant phenotypes is critical. In this study, we conducted a phosphoproteomic analysis of DGC cells possessing Met gene amplification and identified Pleckstrin Homology Domain Containing A5 (PLEKHA5) as a protein that is tyrosine-phosphorylated downstream of Met. Knockdown of PLEKHA5 selectively suppressed the growth of DGC cells with Met gene amplification by inducing apoptosis, even though they had acquired resistance to Met inhibitors. Moreover, PLEKHA5 silencing abrogated the malignant phenotypes of Met-addicted DGC cells, including peritoneal dissemination in vivo. Mechanistically, PLEKHA5 knockdown dysregulates glycolytic metabolism, leading to activation of the JNK pathway that promotes apoptosis. These results indicate that PLEKHA5 is a novel downstream effector of amplified Met and is required for the malignant progression of Met-addicted DGC.

Fibroblast growth factor receptor 2 (FGFR2) has two isoforms: IIIb type and IIIc type. Clinicopathologic significance of these two FGFR2 subtypes in gastric cancer remains to be known. This study aimed to clarify the clinicopathologic difference of FGFR2IIIb and/or FGFR2IIIc overexpression. A total of 562 patients who underwent gastrectomy was enrolled. The expressions of FGFR2IIIb and FGFR2IIIc were retrospectively examined by immunohistochemistry or fluorescence in situ hybridization (FISH) using the 562 gastric tumors. We evaluated the correlation between clinicopathologic features and FGFR2IIIb overexpression and/or FGFR2IIIc overexpression in gastric cancer. FGFR2IIIb overexpression was observed in 28 cases (4.9%), and FGFR2IIIc overexpression was observed in four cases (0.7%). All four FGFR2IIIc cases were also positive for FGFR2IIIb, but not in the same cancer cells. FGFR2IIIb and/or FGFR2IIIc overexpression was significantly correlated with lymph node metastasis and clinical stage. Both FGFR2IIIb and FGFR2IIIc were significantly associated with poor overall survival. A multivariate analysis showed that FGFR2IIIc expression was significantly correlated with overall survival. FISH analysis indicated that FGFR2 amplification was correlated with FGFR2IIIb and/or FGFR2IIIc overexpression. These findings suggested that gastric tumor overexpressed FGFR2IIIc and/or FGFR2IIIb at the frequency of 4.9%. FGFR2IIIc overexpression might be independent prognostic factor for patients with gastric cancer.

Gastric cancer (GC) is the third leading cause among all cancer deaths globally. Although the treatment outcome of GC has improved, the survival of patients with GC at stages III and IV remains unsatisfactory. Among several types of GC, scirrhous type GC (SGC) shows highly aggressive growth and invasive activity, leading to frequent peritoneal metastasis. SGC is well known to accompany abundant stromal cells that compose the tumor microenvironment (TME) along with the produced extracellular matrix (ECM) and secreted factors. One of the main stromal components is cancer associated fibroblast (CAF). In the SGC microenvironment, CAFs are a source of various secreted factors, including fibroblast growth factors (FGFs), which mediate prominent tumor-stimulating activity. In turn, cancer cells also secrete numerous factors, which can activate and educate CAFs. Current findings suggest that cancer cells and stromal cells communicate interactively via the soluble factors, the ECM, and likely also by exosomes. In this review, we focus on the soluble factors mediating communication between cancer cells and CAFs in SGC, and consider how they are related to the modulation of TME and the high rate of peritoneal metastasis. At last, we discuss the perspectives on targeting these communication pathways for improved future treatment.

• cancer associated fibroblast
• fibroblast growth factor receptor
• gastric cancer
• scirrhous carcinoma of the stomach
• transforming growth factor β1
• tumor microenvironment

• Cancer research
• Cell culture
• Silica fiber
• Three-dimensional culture system
• Tissueoid

• FGF
• FGFR
• gastric cancer
• monoclonal antibody
• small molecule

• Animals
• Carcinogenesis/genetics
• Fibroblast Growth Factors/metabolism
• Humans
• Oncogenes
• Receptors, Fibroblast Growth Factor/metabolism
• Signal Transduction
• Stomach Neoplasms/genetics

• contributing factors
• diffuse gastric cancer
• gastric cancer
• hereditary diffuse gastric cancer

• Germ-Line Mutation/genetics
• Helicobacter Infections/pathology
• Humans
• Models, Biological
• Neoplasm Proteins/metabolism
• Stomach Neoplasms/genetics
• Stomach Neoplasms/microbiology
• Stomach Neoplasms/pathology

Fibroblast growth factor receptors (FGFRs) are promising targets for antibody-based cancer therapies, as their substantial overexpression has been found in various tumor cells. Aberrant activation of FGF receptor 2 (FGFR2) signaling through overexpression of FGFR2 and/or its ligands, mutations, or receptor amplification has been reported in multiple cancer types, including gastric, colorectal, endometrial, ovarian, breast and lung cancer. In this paper, we describe application of the phage display technology to produce a panel of high affinity single chain variable antibody fragments (scFvs) against the extracellular ligand-binding domain of FGFR2 (ECD_FGFR2). The binders were selected from the human single chain variable fragment scFv phage display libraries Tomlinson I + J and showed high specificity and binding affinity towards human FGFR2 with nanomolar K_D values. To improve the affinity of the best binder selected, scFvF7, we reformatted it to a bivalent diabody format, or fused it with the Fc region (scFvF7-Fc). The scFvF7-Fc antibody construct presented the highest affinity for FGFR2, with a K_D of 0.76 nM, and was selectively internalized into cancer cells overexpressing FGFR2, Snu-16 and NCI-H716. Finally, we prepared a conjugate of scFvF7-Fc with the cytotoxic drug monomethyl-auristatin E (MMAE) and evaluated its cytotoxicity. The conjugate delivered MMAE selectively to FGFR2-positive tumor cells. These results indicate that scFvF7-Fc-vcMMAE is a highly potent molecule for the treatment of cancers with FGFR2 overexpression.

• Cell Line, Tumor
• Endocytosis
• Enzyme-Linked Immunosorbent Assay
• Gastrointestinal Neoplasms/therapy
• Humans
• Receptor, Fibroblast Growth Factor, Type 2/genetics
• Single-Chain Antibodies/metabolism
• Surface Plasmon Resonance

• National Science Centre, Poland
• European Regional Development Fund (Operational Programme Innovative Economy, 1.1.2)

• FGFR2
• S-1
• gastric cancer
• recurrence timing
• survival outcomes

Inhibitor of kappa B kinase epsilon (IKKε) and TANK-binding kinase 1 (TBK1) are non-canonical IKKs. IKKε and TBK1 share the kinase domain and are similar in their ability to activate the nuclear factor-kappa B signaling pathway. IKKε and TBK1 are overexpressed through multiple mechanisms in various human cancers. However, the expression of IKKε and TBK1 in gastric cancer and their role in prognosis have not been studied.

To investigate overexpression of the IKKε and TBK1 proteins in gastric cancer and their relationship with clinicopathologic factors, we performed immunohistochemical staining using a tissue microarray. Tissue microarray samples were obtained from 1,107 gastric cancer patients who underwent R0 gastrectomy with extensive lymph node dissection and adjuvant chemotherapy.

We identified expression of IKKε in 150 (13.6%) and TBK1 in 38 (3.4%) gastric cancers. Furthermore, co-expression of IKKε and TBK1 was identified in 1.5% of cases. Co-expression of IKKε and TBK1 was associated with differentiated intestinal histology and earlier T stage. In a multivariate binary logistic regression model, intestinal histologic type by Lauren classification and early AJCC stage were significant predictors for expression of IKKε and TBK1 proteins in gastric cancer. Changes in IKKε and TBK1 expression may be involved in the development of intestinal-type gastric cancer. The overexpression of IKKε and TBK1 should be considered in selected patients with intestinal-type gastric cancer.

In conclusion, this is the first large-scale study investigating the relationships between expression of IKKε and TBK1 and clinicopathologic features of gastric cancer. The role of IKKε and TBK1 in intestinal-type gastric cancer pathogenesis should be elucidated by further investigation.

• IKKε
• TBK1
• cancer
• gastric
• therapy

Receptor tyrosine kinases promote tumor progression in many cancers, although oncologic activation differs between diffuse-type gastric cancer (DGC) and intestinal-type gastric cancer (IGC). Fibroblast growth factor receptor (FGFR) is one RTK, and we previously reported the clinical significance of FGFR1, 2, 3, and 4 in gastric cancer. The aim of the present study was to reevaluate the clinical significance of FGFR1–4 expression separately in DGC and IGC.

Tumor samples, including 109 DGCs and 100 IGCs, were obtained from patients who underwent gastrectomy between 2003 and 2007 in our institution. The expression levels of FGFR1, 2, 3, and 4 were measured in the tumors by immunohistochemical analysis.

In DGC, high expression of FGFR1, FGFR2, or FGFR4 was significantly associated with the depth of invasion, lymph-node metastasis, pathological stage, and distant metastasis or recurrent disease. Patients with high expression of FGFR1, FGFR2, or FGFR4 had significantly poorer disease-specific survival (DSS) (p = 0.009, p = 0.001, and p = 0.023, respectively). In IGC, only FGFR4 expression was significantly associated with factors relative to tumor progression and with shorter DSS (p = 0.012).

In conclusion, high FGFR4 expression correlated with tumor progression and survival in both DGC and IGC, whereas high expression of FGFR1 and 2 correlated with tumor progression and survival in only DGC.

• Fibroblast growth factor receptor 1
• Fibroblast growth factor receptor 2
• Fibroblast growth factor receptor 3
• Fibroblast growth factor receptor 4
• Gastric cancer
• Immunohistochemistry

Several novel fusion transcripts were identified by next-generation sequencing in gastric cancer; however, the breakpoint junctions have yet to be characterized. The present study characterized a plethora of APIP-FGFR2 genomic breakpoints in the SNU-16 gastric cancer cell line, which harbored homogeneously staining regions (hsrs) and double minute chromosomes. Oligonucleotide microarrays revealed high-level amplifications at chromosomes 8q24.1 (0.8 Mb region), 10q26 (1.1 Mb) and 11p13 (1.1 Mb). These amplicons contained MYC and PVT1 at chromosome 8q24.1, BRWD2, FGFR2 and ATE1 at chromosome 10q26, and 24 genes, including APIP, CD44, RAG1 and RAG2, at chromosome 11p13. Based on these findings, reverse transcription-polymerase chain reaction (PCR) was performed using various candidate gene primers to detect possible fusion transcripts, and several products using primer sets for the APIP and FGFR2 genes were detected. Eventually, three in-frame and two out-of-frame fusion transcripts were detected. Notably, PCR analysis of the entire genomic DNA detected three distinct genomic junctions. The breakpoints were within intron 5 of APIP, which contained three distinct breakpoints, and introns 5, 7 and 9 of FGFR2. Fluorescence in situ hybridization showed several fusion signals within hsrs using two short probes (~10-kb segments of a bacterial artificial chromosome clone) containing exons 2–5 of APIP or exons 11–13 of FGFR2. Although, for any given fusion, a multiplicity of transcripts is thought to be created by alternative splicing of one rearranged allele, the results of the present study suggested that genomic fusions of APIP and FGFR2 are generated in hsrs with a diversity of breakpoints that are then faithfully transcribed.

• APIP
• FGFR2
• gastric cancer
• genomic amplification
• homogenously staining region

• Adult stem cell
• Colon
• Development
• Gut
• Organoid
• Small intestine
• Stomach

• Chromosomal instability
• Early-onset gastric cancer
• Epigenetic alterations
• Gastric cancer
• Loss of heterozygosity
• Microsatellite instability
• Molecular alterations
• Single-nucleotide polymorphism

• Adult
• Age of Onset
• Animals
• Biomarkers, Tumor/genetics
• Biomarkers, Tumor/metabolism
• Epigenesis, Genetic
• Gene Expression Regulation, Neoplastic
• Gene-Environment Interaction
• Genetic Predisposition to Disease
• Heredity
• Humans
• Microsatellite Instability
• Middle Aged
• Mutation
• Pedigree
• Phenotype
• Polymorphism, Single Nucleotide
• Prognosis
• Risk Factors
• Signal Transduction
• Stomach Neoplasms/genetics
• Stomach Neoplasms/metabolism
• Stomach Neoplasms/pathology

• Clinical application of FGF
• Fibroblast growth factor
• Heparan sulfate
• Klotho
• Receptor tyrosine kinase

• fibroblast growth factor receptor
• gastric cancer
• immunohistochemical analysis

• FGFR2b
• GVHD
• KGF
• cytoprotection
• epithelial repair
• immune reconstitution
• mucositis
• palifermin
• pericardial adhesions
• pre-synaptic organizing molecules
• pulmonary injury
• regeneration
• urothelium
• wound healing

Diffuse-type gastric carcinomas (DGC) exhibit more aggressive progression and poorer prognosis than intestinal-type and other gastric carcinomas. To identify potential therapeutic targets, we examined protein tyrosine phosphorylation in a panel of DGC and other gastric cancer cell lines. Protein tyrosine phosphorylation was significantly enhanced or altered in DGC cell lines compared with that in other gastric cancer cell lines. Affinity purification and mass spectrometry analysis of tyrosine-phosphorylated proteins identified Met as a protein that is preferentially expressed and phosphorylated in DGC cell lines. Unexpectedly, Met inhibitors blocked cell growth, Met downstream signaling and peritoneal dissemination in vivo in only a subset of cell lines that exhibited remarkable overexpression of Met. Likewise, only cell lines with overexpression of fibroblast growth factor receptor 2 (FGFR2) or phosphorylation of FRS2 were sensitive to an FGFR2 inhibitor. A Src inhibitor saracatinib impaired growth in cell lines that are insensitive to both Met and FGFR2 inhibitors. Saracatinib also effectively impaired peritoneal dissemination of Met-independent and FGFR2-independent SGC cells. Moreover, DGC cell lines exhibited nearly mutually exclusive susceptibility to Met, FGFR and Src inhibitors. These results suggest that DGC have distinct sensitivities to molecular target drugs and that targeting Src is beneficial in the treatment of DGC insensitive to Met and FGFR inhibition.

• c-Met
• c-src
• neoplasm metastasis
• saracatinib
• stomach neoplasms

• Antineoplastic Agents/pharmacology
• Benzamides/pharmacology
• Breast Neoplasms/drug therapy
• Cell Line, Tumor
• Drug Resistance, Neoplasm/genetics
• Female
• Humans
• Multiple Myeloma/drug therapy
• Multiple Myeloma/genetics
• Mutation
• Neoplasms/drug therapy
• Piperazines/pharmacology
• Pyrazoles/pharmacology
• Pyrimidines/pharmacology
• Receptor Protein-Tyrosine Kinases/antagonists & inhibitors
• Receptor Protein-Tyrosine Kinases/drug effects
• Receptor, Fibroblast Growth Factor, Type 1/antagonists & inhibitors
• Receptor, Fibroblast Growth Factor, Type 1/metabolism
• Receptor, Fibroblast Growth Factor, Type 2/antagonists & inhibitors
• Receptor, Fibroblast Growth Factor, Type 2/metabolism
• Receptor, Fibroblast Growth Factor, Type 3/antagonists & inhibitors
• Receptor, Fibroblast Growth Factor, Type 3/genetics
• Receptors, Fibroblast Growth Factor/antagonists & inhibitors
• Receptors, Fibroblast Growth Factor/metabolism
• Signal Transduction/drug effects
• Stomach Neoplasms/drug therapy
• Urinary Bladder Neoplasms/drug therapy

• BBS/E/B/0000C199 Biotechnology and Biological Sciences Research Council
• BBS/E/B/0000C235 Biotechnology and Biological Sciences Research Council
• BBS/E/B/000C0417 Biotechnology and Biological Sciences Research Council
• BBS/E/B/000C0419 Biotechnology and Biological Sciences Research Council

• Advanced gastric cancer
• angiogenic pathway
• biomarker
• epidermal growth factor pathway
• targeted therapy

• Adenocarcinoma/genetics
• Adenocarcinoma/mortality
• Adenocarcinoma/pathology
• Biomarkers, Tumor/analysis
• Gene Amplification
• Humans
• In Situ Hybridization, Fluorescence
• Kaplan-Meier Estimate
• Neoplasm Staging
• Proportional Hazards Models
• Real-Time Polymerase Chain Reaction
• Receptor, Fibroblast Growth Factor, Type 2/genetics
• Reverse Transcriptase Polymerase Chain Reaction
• Stomach Neoplasms/genetics
• Stomach Neoplasms/mortality
• Stomach Neoplasms/pathology
• Tissue Array Analysis

Frequency of FGFR2 amplification, its clinicopathological features, and the results of high-throughput screening assays in a large cohort of gastric clinical samples remain largely unclear.

Drug sensitivity to a fibroblast growth factor receptor (FGFR) inhibitor was evaluated in vitro. The gene amplification of the FGFRs in formalin-fixed, paraffin-embedded (FFPE) gastric cancer tissues was determined by a real-time PCR-based copy number assay and fluorescence in situ hybridisation (FISH).

FGFR2 amplification confers hypersensitivity to FGFR inhibitor in gastric cancer cell lines. The copy number assay revealed that 4.1% (11 out of 267) of the gastric cancers harboured FGFR2 amplification. No amplification of the three other family members (FGFR1, 3 and 4) was detected. A FISH analysis was performed on 7 cases among 11 FGFR2-amplified cases and showed that 6 of these 7 cases were highly amplified, while the remaining 1 had a relatively low grade of amplification. Although the difference was not significant, patients with FGFR2 amplification tended to exhibit a shorter overall survival period.

FGFR2 amplification was observed in 4.1% of gastric cancers and our established PCR-based copy number assay could be a powerful tool for detecting FGFR2 amplification using FFPE samples. Our results strongly encourage the development of FGFR-targeted therapy for gastric cancers with FGFR2 amplification.

• Fibroblasts
• Growth factor
• Interaction
• Microenvironment
• Scirrhous gastric cancer
• Stromal cells

• Cytogenetic Analysis
• Epigenesis, Genetic
• Genes, Neoplasm
• Humans
• Loss of Heterozygosity
• Stomach Neoplasms/diagnosis
• Stomach Neoplasms/genetics

• Acrocephalosyndactylia/genetics
• Adolescent
• Antineoplastic Combined Chemotherapy Protocols/therapeutic use
• Carboplatin/administration & dosage
• Chromosome Aberrations
• Combined Modality Therapy
• Dysgerminoma/drug therapy
• Dysgerminoma/genetics
• Dysgerminoma/surgery
• Etoposide/administration & dosage
• Female
• Humans
• In Situ Hybridization, Fluorescence
• Neoplasm Proteins/genetics
• Neoplasm Proteins/physiology
• Neoplastic Syndromes, Hereditary/genetics
• Nucleic Acid Hybridization
• Ovarian Neoplasms/drug therapy
• Ovarian Neoplasms/genetics
• Ovarian Neoplasms/surgery
• Ovariectomy
• Point Mutation
• Receptor, Fibroblast Growth Factor, Type 2/genetics
• Receptor, Fibroblast Growth Factor, Type 2/physiology
• Remission Induction

• Animals
• Blotting, Northern
• Breast Neoplasms/genetics
• Breast Neoplasms/metabolism
• Cell Line, Tumor
• Cell Transformation, Neoplastic/genetics
• Cell Transformation, Neoplastic/metabolism
• Female
• Gene Amplification
• Gene Expression/drug effects
• Gene Expression Regulation, Neoplastic/drug effects
• Gene Expression Regulation, Neoplastic/physiology
• Humans
• Mice
• Neoplasm Proteins/genetics
• Neoplasm Proteins/metabolism
• Oligonucleotide Array Sequence Analysis
• Pyrimidines/pharmacology
• RNA, Messenger/analysis
• RNA, Small Interfering
• Receptor, Fibroblast Growth Factor, Type 2/metabolism
• Reverse Transcriptase Polymerase Chain Reaction
• Signal Transduction/physiology
• beta Catenin/genetics
• beta Catenin/metabolism

• R01 CA100724 NCI NIH HHS
• R01 CA70354 NCI NIH HHS

• Administration, Oral
• Animals
• Antineoplastic Agents/administration & dosage
• Antineoplastic Agents/pharmacology
• Antineoplastic Agents/therapeutic use
• Cell Line, Tumor
• Cell Proliferation/drug effects
• Dimerization
• Gefitinib
• Humans
• Mice
• Mice, Inbred Strains
• Quinazolines/administration & dosage
• Quinazolines/pharmacology
• Quinazolines/therapeutic use
• RNA, Small Interfering/pharmacology
• Receptor, Fibroblast Growth Factor, Type 2/analysis
• Receptor, Fibroblast Growth Factor, Type 2/antagonists & inhibitors
• Receptor, Fibroblast Growth Factor, Type 2/metabolism
• Stomach Neoplasms/drug therapy
• Stomach Neoplasms/enzymology
• Up-Regulation/drug effects
• Xenograft Model Antitumor Assays