膀胱癌组织FGFR3基因突变和蛋白表达与预后关系研究

Prognostic value of mutation and protein overexpression of FGFR3 in bladder cancer

目的成纤维细胞生长因子受体3(fibroblast growth factor receptor 3,FGFR3)与膀胱癌的发生发展密切相关,然而其临床病理意义尚未明确,尤其是预后关系。本研究探讨FGFR3基因突变和蛋白表达与膀胱癌预后的关系。方法采用Sanger测序方法分析南京中医药大学张家港附属医院泌尿外科2014-02-01-2017-12-31的84例膀胱癌组织FGFR3基因热点突变外显子7、10和15,同时采用免疫组化方法检测FGFR3蛋白表达。应用Kaplan-Meier方法进行生存分析。通过多因素COX模型方法对可能影响膀胱癌预后的因素进行分析。结果FGFR3基因突变率为16.67%(14/84),蛋白表达率为28.57%(24/84)。FGFR3基因突变在不同年龄组、吸烟史、分级、大小以及肿瘤是否复发差异有统计学意义,均P<0.05。FGFR3基因突变和蛋白表达一致性为35.71%(5/14),但二者无关联,χ~2=0.42,P=0.52。Kaplan-Meier生存曲线分析提示,FGFR3基因突变(χ~2=1.62,P=0.20)和蛋白表达(χ~2=0.01,P=0.93)不影响总生存期(overall survival,OS),FGFR3蛋白表达(χ~2=0.80,P=0.37)也不影响无瘤生存期(disease-free survival,DFS),但FGFR3基因突变型膀胱癌的DFS比野生型降低,差异有统计学意义,χ~2=5.21,P=0.02。多参数COX回归分析影响膀胱癌OS和DFS,各临床参数和FGFR3均不是OS的独立影响因素,而FGFR3基因突变则是DFS的独立影响因素,且FGFR3基因突变为危险因素,HR=9.169,95%CI为2.641~31.835,P<0.001。结论 FGFR3基因在低级别膀胱癌中易突变和易复发,DFS短,应加强监测。

OBJECTIVE Alterations in fibroblast growth factor receptor 3(FGFR3)have been implicated in the pathogenesis of urothelial carcinoma.However,its clinicopathological significance has not been clearly established,especially in prognosis.The purpose of this study was to investigate the mutation and overexpression of FGFR3 in bladder cancer.METHODS Study cohorts included 84 cases of bladder carcinoma of Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine.The mutational analysis of FGFR3 exons 7,10,and 15 was investigated and overexpression of FGFR3 was evaluated.The findings were analyzed for the association with relevant clinicopathological parameters.Kaplan-Meier method was used in survival analysis,multivariate COX model was used to analyze the factors that might affect the prognosis of bladder carcinoma.RESULTS Fourteen cases mutations of FGFR3 were detected(16.67%),24 cases overexpression of FGFR3 were found(28.57%).Comparison of FGFR3 mutations in different age groups,smoking history,grade,size and recurrence,the difference was statistically significant in the mutations of FGFR3,but not in the overexpression of FGFR3.5 cases overexpression of FGFR3 were detected in 14 cases of FGFR3 mutations,but there was no correlation between mutations and overexpression of FGFR3 (χ~2=0.42,P=0.52).According to Kaplan-Meier Survival analysis,overall survival and disease-free survival didn’t differ in the overexpression of FGFR3,and overall survival also didn’t differ between the mutations of FGFR3 and wild types of FGFR3,however the mutations of FGFR3 were significantly associated with shorter disease-free survival(χ~2=5.21,P=0.02).Multivariate Cox proportional hazards model analysis of OS and DFS for the following variables:age,gender,stage and grade of tumor,and FGFR3(overexpression and mutation)revealed that mutations of FGFR3 were adverse predictors of disease-free survival(HR=9.169,95%CI:2.641-31.835,P<0.001).CONCLUSION Mutations of FGFR3 are more common in bladder cancer with low grade.