The Relationship Between The Expression Of C-kit, ETV1, FOXF1 And The Clinicopathology Of Gastrointestinal Stromal Tumors

Background:Gastrointestinal stromal tumors(GISTs)are the most common mesenchymal tumors in gastrointestinal tract.It arises from the interstitial cells of Cajal in gastrointestinal muscular layer,or homologous stem cells.It can arise in any parts of the gastrointestinal tract.About 70%occur in the stomach,10%-25%in the small intestine,and few in the rectum,esophagus and colon.Its morbidity is approximately 10-20/1 million,and account for 1%-3%of all gastrointestinal tumors,80%of gastrointestinal sarcomas.In recent years there has been a marked increase in the morbidity rate.The growth of this tumor is slow and hidden.Therefore,early diagnosis is difficult and the misdiagnosis rate is high.The clinical manifestation is various and uncharacteristic.It is mainly related to the location and the size of the tumor as well as whether rupture occurs.It usually manifests as abdominal discomfort,haematemesis,bloody stools,melena and intestinal obstruction.GISTs are quite insensitive to traditional chemotherapy and radiotherapy.Total resection remains to be the only way to cure GISTs radically.However,tumor recurrence occurs in 40%-80%of the GISTs patients,including local recurrence,peritoneal dissemination and liver metastasis.The interval time between surgery and recurrence ranges between 19?25 months.80%of the recurrence occur within 2 years post-operation.The key process in the forming of GISTs is gene mutation.Most GISTs are related to the acquired mutation of KIT/PDGFRA gene functions.Studies also confirmed that KIT/PDGFRA gene mutations are repelled mutually,namely every GIST acquires only one single gene mutation.80%-85%are c-Kit gene mutations,7%are PDGFRA mutations,10%-15%are wild types(mutations not detected)[9,10].Although the molecular targeted drug,tyrosine kinase receptor inhibitor imatinib,has proved certain effects in clinical use,the drug resistance rate and recurrence rate are increasing due to the phenomena of multiple-site mutations and secondary mutations of the two genes.Recurrence and drug resistance become the key points that affect treatment effects.Subsequent second,third and fourth line targeted therapeutic drugs are characteristic of great side effects and uncertain therapeutic effects.Studies have found that the median progression-free survival of the patients who took imatinib myselate(Gleevc)after surgery is only about 2 years.And the incidence of secondary drug resistance is about 40%-50%.Sunitinib malate(Sutent)is applied in imatinib-resistant patients,but its clinical benefit rate is only 65%(7%improved,58%stable and without any progression).What is worse is the short duration of clinical efficiency and the tendency of drug resistance.Although regorafenib,sorafenib,nilotinib,dasatinib and pazopanib are all effective in imatinib-and sunitinib-resistant patients,they are lacking in precise effects.The bottleneck for the treatment of GISTs is making the researchers to look for new molecular labels and new therapeutic targets.The searching for new therapeutic methods is a current hotspot in GISTs studies.Gene mutation is the key to the formation of GISTs.80%-85%GISTs is related to the functional mutation of KIT gene.ETV1 is a member of the transcription factor ETS family.ETV1 stimulates KIT gene transcription.KIT inhibits the degradation of ETV1 protein through the MEK-MAPK axis.Therefore,the two can regulate the/GISTs gene expression in Cajal cells,which can lead to the continuous activation of the intracellular signal transduction pathway and promote the proliferation and survival of the tumor.FOXF1(Forkhead box protein F1)is a class of transcription factors closely related to embryonic development and tumor development.There is only one literature at home and abroad on the expression of FOXF1 gene in gastrointestinal stromal tumors and its role in GISTs.It is found that FOXF1 is highly expressed in GISTs compared with other sarcoma subtypes,and FOXF1 may be an upstream regulator of KIT and ETV1.Whether the mechanism of FOXF1's occurrence and development in GISTs can serve as a new therapeutic target for GISTs needs further study.In this study,the content of FOXF1 expression in the GISTs(stomach,duodenum,small intestine,rectum)and the normal tissue adjacent to the tumor in different parts of the GISTs was measured.The correlation between the three and the clinicopathological data and prognostic indicators of GISTs patients was analyzed,and the clinical significance of the three patients in the diagnosis and treatment of gastrointestinal stromal tumors was discussed.Use value.Objectives:1.To study the expression level and distribution of c-kit,ETV-1 and FOXF1 in GISTs tumor and adjacent normal tissues and analyze the correlation between them.2.To analyze the correlation between the expression of c-kit,ETV-1 and FOXF1 in tumor tissues and clinicopathological data of GISTs patients.3.To explore the clinical value of c-kit,ETV-1 and FOXF1 in the diagnosis and treatment of gastrointestinal stromal tumors.Results:The expression of c-kit and ETV1 in the gastrointestinal stromal tissues of 66 cases of gastrointestinal stromal tumors and normal tissues was significantly higher than that of normal tissues(the difference was statistically significant,P<0.05),while the expression of FOXF1 in the gastrointestinal stromal tissues was significantly lower than that of the normal group(the difference was statistically significant,P<0.05);The expression of c-kit was related to the location of tumor,and the difference was statistically significant.The expression of ETV-1 was related to the risk of recurrence and abnormal mitosis.The expression of FOXF1 was related to the risk of recurrence,the size of the tumor,the abnormal mitotic image,the Ki-67,and the Desmin,and the difference was statistically significant to the Spearman correlation analysis of FOXF1 and ETV1.C-kit,c-kit,there is a positive correlation between ETV1 and c-kit(correlation coefficient r = 0.251,P = 0.020);there is a positive correlation between ETV1 and FOXF1(correlation coefficient r?0.340,P = 0.001);c-kit and FOXF1 are not related.In terms of the risk of recurrence,the location of the tumor is different,the size of the tumor,the abnormal mitotic image,the Ki-6 index,the expression level of FOXF1 and ETV1 are different,and the NIH risk classification of the GISTs patients is different.Multivariate logistic analysis showed that tumor size and abnormal mitotic figures were independent risk factors for NIH risk classification.Conclusion:1.c-kit,ETV1 and FOXF1were expressed in normal mucosa and stromal tumors,and their expression level was different.2.FOXF1 and ETV-1 have a clear correlation with the clinicopathological features of gastrointestinal stromal tumors.They may serve as a new direction for the molecular targeting of gastrointestinal stromal tumors.3.Tumor location,tumor size and abnormal mitotic figures are independent risk factors for NIH risk classification.