Fibroblast growth factor receptor 2 gene amplification status and its clinicopathologic significance in gastric carcinoma

Jung, Eun-Jung; Jung, Eun Ji; Min, Sun Young; Kim, Min A; Kim, Woo Ho

doi:10.1016/j.humpath.2011.12.002

Cited by 85 publications

(84 citation statements)

References 28 publications

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“…13,18 In this large-scale study with 1974 gastric cancer patients, FGFR2 amplification and FGFR2b overexpression were more commonly identified in poorly differentiated tumors with diffuse histology, which is different from other reports. 4,15 Diffuse histology was found in most tumors with high 15 In this study, although FGFR2 amplification itself was not associated with overall survival, FGFR2b overexpression with high H-score showed strong prognostic value for survival. Considering the controversial clinical significance and high intratumoral heterogeneity of FGFR2 amplification in gastric cancer, 13,18 the extent of FGFR2b overexpression, rather than the presence of FGFR2 amplification itself, may be a better predictor of patient survival.…”

Section: Discussionmentioning

confidence: 49%

“…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.…”

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confidence: 99%

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

et al. 2016

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FGFR2 gene amplification, and resulting FGFR2 protein overexpression, is rare in gastric cancer patients, and development of an accurate and widely available method for mass screening to identify patients who may respond to treatment with fibroblast growth factor receptor (FGFR) inhibitors is important. We first screened 312 gastric cancer patients with known copy number variations by FGFR2b immunohistochemistry using FPR2-D, an isoformspecific antibody. Next, we performed immunohistochemistry on tissue microarrays from 1574 gastric cancer patients. Selected cases were analyzed for FGFR2 amplification by FISH. In addition, FGFR2b overexpression was studied in 88 matched primary and metastatic gastric cancers. In the first cohort, FGFR2b immunohistochemistry results correlated very well with those of copy number variation (r = 0.79) and FISH (r = 1.0). In total, FGFR2b overexpression was identified in 73 of 1974 gastric cancers (4%). The concordance between immunohistochemistry and FISH was extremely high; all 2+ and 3+ cases identified by immunohistochemistry were FGFR2 amplified. In the matched primary and metastatic gastric cancer pairs, the positivity and percentage of positive tumor cells were significantly higher in metastatic gastric cancers than in primary gastric cancers (8% vs 3% and 75% vs 47%, respectively; Po0.001). FGFR2b overexpression was significantly more frequent in gastric cancers with diffuse subtype (P = 0.01) and higher N stage (P = 0.006). FGFR2b overexpression with H-score ≥ 150 were independent prognostic factors for overall survival with hazard ratio of 1.836 (95% confidence interval, 1.034-3.261; P = 0.038). FGFR2b positivity in immunohistochemistry was strongly correlated with FGFR2 amplification. Given the low frequency of FGFR2 amplification in gastric cancers, FGFRb2 immunohistochemistry is an accurate screening tool to detect FGFR2 amplification, and both primary and metastatic gastric cancer tissues should be tested to select gastric cancer patients for treatment with FGFR2 inhibitors. Gastric cancer is the second most common cause of cancer-related deaths worldwide, and the prognosis of advanced gastric cancer is still poor. 1 Several large-scaled clinical trials have failed to demonstrate survival benefits of targeted therapeutic agents in patients with metastatic gastric cancer. Nevertheless, the REGARD trial demonstrated significantly longer progression-free survival of gastric cancer patients treated with ramucirumab, a monoclonal antibody against vascular endothelial growth factor receptor 2, compared with that of patients in the placebo group. 2 This was the first trial to demonstrate a meaningful benefit for a monotherapy in metastatic gastric cancer. The RAINBOW trial, which compared the efficacy of paclitaxel with or without ramucirumab in second-line chemotherapy, showed prolonged

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Section: Discussionmentioning

confidence: 49%

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

et al. 2016

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“…Deng et al [21] also described that FGFR2, HER2, EGFR and MET amplification as assessed using an SNP array were mutually exclusive events. Other reports have shown that FGFR2 amplification was found to be mutually exclusive with HER2 or HER2/MET amplifications [22,23]. In summary, although multiple proteins of RTKs were overexpressed simultaneously, gene amplification or a gain in the gene copy number of an RTK was an exclusive event.…”

Section: Discussionmentioning

confidence: 75%

Expression profiles of HER2, EGFR, MET and FGFR2 in a large cohort of patients with gastric adenocarcinoma

et al. 2014

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Background Some tyrosine kinase receptors (RTKs) play critical roles in gastric cancer progression. Not only trastuzumab, but also several other agents targeting RTKs are being investigated for gastric cancer therapy. However, the simultaneous expression of multiple RTKs, which may interfere with the effectiveness of therapeutic agents, has not been evaluated in a large cohort with gastric adenocarcinoma (GAC). Methods We performed a tissue microarray analysis in 950 patients with GAC who underwent a gastrectomy without preoperative chemotherapy. The protein expressions of HER2, EGFR, MET and FGFR2 were evaluated using immunohistochemistry, and the gene amplifications of HER2, EGFR and MET were examined using dual-color in situ hybridization.Results The frequency of overexpression was 11.8 % for HER2, 23.5 % for EGFR, 24.9 % for MET and 31.1 % for FGFR2. Whereas strong staining for each of the RTKs was heterogeneous, tumors with homogeneously strong staining areas often exhibited gene amplification. Strong EGFR expression was significantly associated with a poor outcome, but no prognostic correlations were observed in other RTKs. The overexpression of single and multiple RTKs was observed in 40.4 and 22.7 % of the cases, respectively. HER2, EGFR, MET and FGFR2 predominance was observed in 10.1, 13.9, 16.1 and 22.9 % of the GACs, respectively. Conclusions Approximately two-thirds of patients with GAC exhibited the expression of at least one RTK and would be candidates for targeted therapies. Moreover, one-third of at least one RTK overexspressing cases showed multiple RTKs expression. Our results may be useful for selecting the most suitable patients for each targeted therapy.

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“…5 In particular, FGFR2 and MET, which encode RTKs similar to ERBB2, are considered as strong candidate targets because their amplification is associated with advanced stages, 6,7 and furthermore, the amplification of FGFR2 was preferentially found in a poorly differentiated subtype. 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.…”

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confidence: 99%

“…[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. 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.…”

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

et al. 2015

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The prognosis of patients with gastric carcinomas at an advanced stage still remains dismal, and therefore novel therapeutic modalities are urgently needed. Since the successful targeting of amplified ERBB2 with a humanized monoclonal antibody, the amplified genes of other receptor tyrosine kinases such as EGFR, FGFR2, and MET, as well as those of other cell regulator genes, are being considered as candidate targets of molecular therapy. The aim of the present study was to determine the amplification status of 26 genes, which are frequently amplified in solid cancers, in advanced gastric cancers. A total of 93 formalin-fixed and paraffin-embedded advanced gastric cancer tissues were examined by multiple ligation-dependent probe amplification, and 32 cases with 'gain' or 'amplified' status of 16 genes were further examined for the respective gene amplification by fluorescence in situ hybridization (FISH) and for the respective protein overexpression by immunohistochemistry. The frequencies of gene amplifications in advanced gastric cancers were as follows: ERBB2 (13 cases, 14%), FGFR2 (7 cases, 8%), MYC (7 cases, 8%), TOP2A (7 cases, 8%), MET (4 cases, 4%), MDM2 (4 cases, 4%), CCND1 (3 cases, 3%), FGF10 (2 cases, 3%), and EGFR (1 case, 1%). Amplification of the receptor tyrosine kinases genes occurred in a mutually exclusive manner except for one tumor in which ERBB2 and FGFR2 were both amplified but in different cancer cells. Co-amplification of ERBB2 and MYC, and EGFR and CCND1, in single nuclei but on different amplicons, was confirmed in one case each. Attempts at correlating the FISH status with the immunohistochemical staining pattern showed variable results from complete concordance to no correlation. In conclusion, combination of multiple ligation-dependent probe amplification and FISH analysis is a feasible approach for obtaining the semi-comprehensive genetic information that is necessary for personalized molecular targeted therapy.

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Fibroblast growth factor receptor 2 gene amplification status and its clinicopathologic significance in gastric carcinoma

Cited by 85 publications

References 28 publications

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

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

Expression profiles of HER2, EGFR, MET and FGFR2 in a large cohort of patients with gastric adenocarcinoma

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

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