Identification Of Molecular Targets In Papillary Thyroid Cancers

Objective: Thyroid cancer(TC)is the most common malignancy in the endocrine system with a rapidly increasing incidence in recent years.Papillary thyroid cancer(PTC)derives from follicular epithelial cells,accounts for about 84% of TC.This study examined the expression pattern of molecules in the NF-κB pathway,including CD44,BCL-2,Cyclin D2,cFLIP,IκBα,A20,and ABINs,which are known regulators of tissue invasion and inflammation.They are reported to be involved in human autoimmune diseases,leukemia and lymphomas.This study identified some important molecular targets in PTCs that could be used in clinical diagnostics for selection of targeted therapy drugs to precisely treat individual patients.Materials and methods: Tissues of 20 patients with thyroid papillary carcinoma who underwent thyroidectomy were enrolled.This study compared the expression of the above genes in tumour and the normal adjacent tissue(NAT)of 20 PTC cases by q RT-PCR and immunohistochemistry.Next-generation sequencing technique was used to compare the mutation of the currently known tumor-related gene in PTC tumor tissue and NAT in order to identify tumor-specific molecular targets associated with thyroid cancer.Results: The results indicated a significantly higher expression of CD44 and Cyclin D2 m RNA and protein in PTC tumor than in NAT.Targeted nextgeneration sequencing(NGS)of solid tumor-related genes showed ALK,BRAF,FGFR4,KIT,MYC,and FGFR3 were mutated in PTC cases with a very high frequency(>80%).Interestingly,BRAF V600 E,a well-known PTC molecular marker,was found to be not always a tumor-specific mutation(i.e.,somatic mutation,S-M)but a germline mutation(G-M)in a few PTC cases.In addition to BRAF,the key components of the MAPK pathway such as HRAS,KRAS,NRAS,and RET genes were also found to be frequently mutated(frequency >40%).Furthermore,high frequency mutations of KIT,MYC,and FGFR3 were also detected in these cases,and some of them were identified to be tumor-specific mutations.Conclusions: High expression of CD44 and Cyclin D2 in NF-κB signaling pathways,as well as high-frequency mutations in ALK,BRAF,FGFR4,KIT,MYC,FGFR3,and MAPK signaling pathways may be involved in the development of papillary thyroid cancer...