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Association of fibroblast growth factor receptor 1 gene amplification with poor survival in patients with esophageal squamous cell carcinoma.

ABSTRACT: To investigate whether FGFR1 gene amplification is associated with clinicopathologic characteristics and its potential impact on survival in patients with resected esophageal squamous cell carcinoma (ESCC).Five hundred fifty-six ESCC patients undergoing curative resection of ESCC were retrospectively studied. FGFR1 gene copy number was determined in microarrayed tumor samples using fluorescent in situ hybridization (FISH) analysis. FGFR1 gene amplification status was prespecified as copy number ? 6 or FGFR1/CEN 8 ratio ? 2.2. FGFR1 expression was evaluated by immunohistochemistry. Overall survival (OS) and disease-free survival (DFS) were analyzed using the Kaplan-Meier method followed by the log rank test. Correlation with survival was examined using multivariate Cox regression.FGFR1 amplification was identified in 67 (12.1%) patients; these patients had significantly shorter OS (50.0 vs 32.0 months; log rank; P<0.001) as well as shorter DFS (47.0 vs 28.0 months; log rank; P<0.001) than those without FGFR1 amplification. Under a Cox proportional hazard model, FGFR1 amplification was associated with significantly shorter OS (adjusted hazard ratio [AHR]=1.61; 95% CI, 1.10-2.43, P=0.004) and DFS (AHR=1.72; 95%CI, 1.15-2.48; P<0.001). Moreover, cases with high intratumoral FGFR1 expression showed significantly shorter OS and DFS than those with low FGFR1 expression. The frequency of FGFR1 amplification was significantly higher in heavy drinkers than in moderate and light drinkers.FGFR1 amplification is an independent adverse prognostic factor in surgically resected ESCC. FGFR1 may be a promising therapeutic target in patients with ESCC.

SUBMITTER: Wang D

PROVIDER: S-EPMC5687652 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Association of fibroblast growth factor receptor 1 gene amplification with poor survival in patients with esophageal squamous cell carcinoma.

Wang Dong D Du Licheng L Wang Zhou Z Liu Xiangyan X Qin Yejun Y Wang Qiangxiu Q Yang Zhe Z Yao Zhigang Z Shi Mo M Shang Bin B Jia Yang Y Chen Huaxia H Qiao Liang L Wang Xueqing X Xiao Zhaohua Z Liu Zhenchuan Z

Oncotarget 20171004 51

<h4>Purpose</h4>To investigate whether <i>FGFR1</i> gene amplification is associated with clinicopathologic characteristics and its potential impact on survival in patients with resected esophageal squamous cell carcinoma (ESCC).<h4>Methods</h4>Five hundred fifty-six ESCC patients undergoing curative resection of ESCC were retrospectively studied. <i>FGFR1</i> gene copy number was determined in microarrayed tumor samples using fluorescent <i>in situ</i> hybridization (FISH) analysis. <i>FGFR1</i ...[more]

PMID: 29179482

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Project description:Cutaneous squamous cell carcinoma (cSCC) is a keratinocyte-derived invasive and metastatic tumor of the skin. It is the second-most commonly diagnosed form of skin cancer striking 200 000 Americans annually. Further, in organ transplant patients, there is a 65- to 100-fold increased incidence of cSCC compared to the general population. Excision of cSCC of the head and neck results in significant facial disfigurement. Therefore, increased understanding of the mechanisms involved in the pathogeneses of cSCC could identify means to prevent, inhibit, and reverse this process. In our previous studies, inhibition of fibroblast growth factor receptor (FGFR) significantly decreased ultraviolet B-induced epidermal hyperplasia and hyperproliferation in SKH-1 mice, suggesting an important role for FGFR signaling in skin cancer development. However, the role of FGFR signaling in the progression of cSCC is not yet elucidated. Analysis of the expression of FGFR in cSCC cells and normal epidermal keratinocytes revealed protein overexpression and increased FGFR2 activation in cSCC cells compared to normal keratinocytes. Further, tumor cell-specific overexpression of FGFR2 was detected in human cSCCs, whereas the expression of FGFR2 was low in premalignant lesions and normal skin. Pretreatment with the pan-FGFR inhibitor; AZD4547 significantly decreased cSCC cell-cycle traverse, proliferation, migration, and motility. Interestingly, AZD4547 also significantly downregulated mammalian target of rapamycin complex 1 and AKT activation in cSCC cells, suggesting an important role of these signaling pathways in FGFR-mediated effects. To further bolster the in vitro studies, NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ mice with SCC12A tumor xenografts treated with AZD4547 (15 mg/kg/bw, twice weekly oral gavage) exhibited significantly decreased tumor volume compared to the vehicle-only treatment group. The current studies provide mechanistic evidence for the role of FGFR and selectively FGFR2 in the early progression of cSCC and identifies FGFR as a putative therapeutic target in the treatment of skin cancer.

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Association of fibroblast growth factor receptor 1 gene amplification with poor survival in patients with esophageal squamous cell carcinoma.

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Association of fibroblast growth factor receptor 1 gene amplification with poor survival in patients with esophageal squamous cell carcinoma.

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