The Study Between Polymorphisms Of PTPN11 And Gastric Cancer Survival

Gastric cancer(GC)is the fifth most common cancer and the third leading cause of cancer death with about 952.000 new cases and 723.000 deaths in 2012 worldwide.Since a steady decline in gastric cancer morbidity and mortality have been observed in developed countries,but the disease burden remains heavy in China.There were 424,000 new gastric cancer cases and 298,000 gastric cancer deaths in China in 2012.Over 40% of the cases occur in China.Although radical gastrectomy has been regarded as one of the most effective treatments,the prognosis of GC patients remain poor.In China,the five years survival rate of GC patients is only 27.4%.Oncogene protein-tyrosine phosphatase nonreceptor-type 11(PTPN11)gene encodes srchomology two domain-containing protein tyrosine phosphatase Shp2,which function as phospho-tyrosine binding domains.Overexpression of Shp2 in cancer tissues is correlated with cancer metastasis,resistance to targeted therapy,and poor prognosis.Recently studies have shown that PTPN11 polymorphism is associated with a variety of human tumors,however,most of the previous works published only focus on the role of SNPs in the carcinogensis,less attention was paid to the evaluation of tumor prognosis.Objective: This study aimed to investigate the association between the single nucleotide polymprphisms(SNPs)of PTPN11 and the long-term survival of GC patients in northern China,and explore the effects of PTPN11 polymorphism on SHP2 protein expression.Methods: From June 2008 to November 2010,388 patients who underwent tumor resection and pathologically diagnosed as gastric cancer from the First Hospital of Jilin University were selected.Five SNPs(rs2301756、rs12423190、rs12229892、rs4767860 and rs7958372)of PTPN11 were genotyped by Taq Man assays.The expression of SHP2 protein were carried out in 93 of gastric cancer specimens using immunohistochemical method.Survival curves of the GC patients within each SNP and pathologic features were plotted by Kaplan-Meier and compared by log-rank test.Harzard ratios(HRs)with their 95% confidence intervals(CIs)were calculated by univariate and multivariate Cox regression model.Results:(1)A total of 363 GC patients were enrolled in survival analysis,the median follow-up time was 60.7 months.In univariate Cox regression analysis,patients carrying rs2301756 CT genotype tended to live longer than those carrying the CC genotype(HR=1.78,95%CI: 1.26-2.52,P=0.001).Patients with tumor size ≥5cm(P<0.001),T3/T4(P<0.001),N2/N3(P<0.001),TNM II or III(P<0.05),vessel invasion(P<0.001)and perineural invasion(P<0.001)had poor overall survival.(2)Muitivariate Cox regression showed that patients carring rs 2301756 CT genotype was associated with poor prognosis and higher risk of death compared with CC genotype carriers,but the difference was not statistically significantly(HR=1.40,95%CI: 0.98-2.00,P=0.064).The sigificant association between the other four SNPs and prognosis of GC were not found.Finally,in multivariate Cox regression model,higher TNM stages(II/III)were independent risk factors for overall survival.(3)No significant difference were found between the genotypes of the five SNPs and the expression levels of SHP2 protein.(P>0.05).Conclusion: No significant association was found between PTPN11 polymorphism and overall survival of GC.PTPN11 rs2301756 gene polymorphism may serve as a biomarker for long-term survival prediction in patients with gastric cancer,but still needs to be followed for long-term follow-up in large sample populations.