| Background and purposeGastrointestinal stromal tumors(GISTs)are the most frequent mesenchymal tumors of digestive tract,characterized by gain of function mutations in either KIT or platelet-derived growth factor receptor alpha.Mutations of c-kit gene have been used for diagnostic assessment and predicting the effects of imatinib.GISTs with KIT exon 11 mutation was a poor prognosis factor by researches.It had been reported that GISTs with KIT exon 11 mutation showed more frequent recurrences,invasion and metastasis.However,not all GISTs with KIT exon 11 mutation showed such malignant behavior,and its poor prognosis had deemed to be more likely related to exon 11 mutation subtypes in a small amount of researches.At present,the relationship between different mutation types and clinicopathological feature of GISTs is still unclear.This study detected KIT gene mutation in GISTs patients by PCR,depicting the the frequency,spectrum and discussing the prognostic value of KIT exon 11 different mutation types of GISTs.Patients and MethodsWe assessed the information of 188 GISTs patients with KIT exon 11 mutation,diagnosed by histopathology and direct sequencing of PCR products,who were from The First Affiliated Hospital Of ZhengZhou University From January 2013 to December 2017 and underwent complete surgical resection.The inclusion criteria for further analysis: GISTs with KIT exon 11 mutations;complete tumor resection;complete clinicopathological data and follow-up data obtained.The exclusion criteria: Double exon mutations;previous chemoradiotherapy;the very low recurrence risk;patients who find a second tumor at the same time or after the diagnosis of GISTs;accompanied by serious cardiovascular or mental illness;other diseases were not suitable for surgery or systemic failure.The frequency,spectrum of different mutation types and clinicopathological characteristics of exon 11 patients were described.All statistical analyses for 188 cases were performed by using Statistical Package for the Social Sciences(SPSS)for Windows version 22.0.Chi-square test or Fisher’s exact tests in cross tables were carried out to analyze the relationships between the mutation types of KIT exon 11 and the clinicopathological features.COX univariate analysis was used to analyze the association between clinicopathological characteristics of GISTs with KIT exon 11 mutations and relapse-free survival(RFS).Survival curves were drawn according to the Kaplan-Meier method and were compared by the log-rank test.Identifying the independent predictors of recurrence was based on COX proportional hazards model.All P values reported were three decimal places behind,and statistical significance was defined at P<0.05.Results1.The type and frequency of KIT exon 11 were including point mutation(36.7%,69/188),deletion(31.9%,60/188),mixed mutation(deletion-insertion)(23.4%,44/188),insertion(4.8%,9/188),and tandem repeat mutation(3.2%,6/188).The common of point mutation was codon 557,559 and 560,with most mutation was codon 559(36.2%,25/69),followed by codon 557(23.2%,16/69),codon 560(17.4%,12/69)and codon 576(8.7%,6/69),with the least of codon 553 and 579(two and one,respectively).Among them,the common mutation forms of codon 559 mutation wereV559D(27.5%,19/69),V559A(10.1%,7/69),V559G(5.8%,4/69),V559E(1.4%,1/69)and V559H(1.4%,1/69).Common mutation forms of codon 557 mutation were W557R(18.8%,13/69)and W557G(4.3%,3/69).The common mutation forms of codon 560 mutation were V560D(14.5%,10/69)and V560G(2.9%,2/69).The form of codon 576 mutation was L576P(8.7%,6/69).The rare mutations were Y553 D,Y553N,and P577 S,one case each.One case of simultaneous point mutation of E554 K and V555 P,and one case of simultaneous point mutation of P551 T and Y553 C.Deletion was mainly concentrated between codon 550 and 560,in the 5’-end of KIT juxtamemberane domain,accounting for about 66.7%(40/60),of which 557-558 deletion was mostly observed(18.3%,11/60),followed by 559 deletion(10.0%,6/69)and 555-558 deletion(6.7%,4/60).Codon 551-554,557-561,558-559 and 579 deletion accounted for about 5.0%(3/60),respectively.The mixed mutation was variable in forms,with the most common mutation site being codon 557-558(15.9%,7/44),followed by codon 550-555(6.8%,3/44)and codon 550-553(4.5%,2/44),codon 556-565(4.5%,2/44),and codon 558-561(4.5%,2/44).The insertion and tandem repeat mutation sites and forms were also variable.The insertion sites were laocated in codon 570-580,among which codon 576-577 was the most common(33.3%,3/9),followed by codon 575-576(22.2%,2/9).The tandem repeat mutation site was mainly concentrated in codon 570-590,one case each.2.Point mutation of KIT exon 11 GISTs mostly occurred in stomach(68.1% vs 51.0%,P=0.028),with low mitotic count(< 5/50HPF)(53.6% vs 34.6%,P=0.018)and moderate risk of recurrence(40.6% vs 23.1%,P=0.013)more common.Deletion and mixed mutation of KIT exon 11 GISTs occurred mostly in the non-gastric(49.0% vs 31.9%,P=0.028),with high mitotic count(≥5/50HPF)(65.4% vs 43.5%,P=0.018)and high risk of recurrence(61.5% vs 43.1%,P=0.013).3.The factors for poor prognosis were as follows by univariate analysis: tumor diameter >5cm(RR=7.857,95%CI:1.014~52.126,P=0.039),high mitotic count(>5/50HPF)(RR=5.031,95%CI:1.120~22.597,P=0.035),high recurrence risk(RR=3.758,95%CI:1.750~17.731,P=0.030),deletion and mixed mutation(RR=6.435,95%CI:1.491~27.714,P=0.012).Multivariate analysis demonstrated that high recurrence risk(RR=7.672,95%CI:1.321~9.437,P=0.023)was an independent adverse prognostic factor.Conclusion1.The mutation forms and sites of KIT exon 11 were complex and variable,with point mutation being the most common,followed by deletion.2.GISTs with point mutation of KIT exon 11 mostly occurred in stomach,with low mitotic count(< 5/50HPF)and moderate risk of recurrence more common.GISTs with Deletion and mixed mutation of KIT exon 11 occurred mostly in the non-gastric,with high mitotic count(≥5/50HPF)and high risk of recurrence.3.Tumor diameter,high recurrence risk,deletion and mixed mutation were the adverse prognostic factors for RFS of KIT exon 11 mutant GISTs. |
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