EGFR Exon 19 Deletion And Its Role In The Development And Progression Of Malignant Thyroid Tumor

Objective: To investigate the impact and mechanism of EGFR exon 19 deletion in the development and progression of malignant thyroid tumor.Methods: The malignant transformation was examined by wound-healing,transwell,soft agar colony formation,and anoikis assays.m RNA levels of differentially expressed genes were analyzed by RNA-seq.Results: Two cases of EGFR mutation were found among the 50 thyroid cancer patients and results suggest that EGFR exon 19 deletion could transform human normal thyroid follicular epithelial cells in an EGF-dependent manner.Data of RNA-seq from the two genetically engineered cell lines(control HTFEC and HTFEC-ex19 del)indicate that the EGFR exon 19 deletion could impact the oncogene KRAS pathway,cancer-related signal pathway,epithelial-mesenchymal transformation pathway,and PI3K-AKT signal pathway downstream of EGFR.Moreover,the genes associated with the thyroid functions were significantly down-regulated,while mesenchymal phenotypic genes in EMT were up-regulated,and they were involved in the composition of cells and extracellular matrix and protein binding function.Our study showed that a thyroid-derived lung cancer patient harboring the EGFR exon 19 deletion had a significant delay of the disease progression when treated with a first-generation EGFR inhibitor(Icotinib).Conclusion: EGFR exon 19 deletion can lead to malignant transformation of human normal thyroid follicular epithelial cells and result in activation of PI3K-AKT pathway,changes of the expression of EMT,and other oncogenic genes,and the impairment of thyroid function.As the thyroid hormone synthesis-related genes play an important role in the occurrence and development of thyroid tumor,targeting the EGFR exon 19 deletion mutation may be exploited as a potential therapeutic strategy for malignant thyroid tumor.