Investigation of somatic mutation in BRAF, CDKN2A, c-KIT e PI3KCA genes as a second hit in sporadic and RET-positive familial medullary thyroid Carcinoma

Abstract

Medullary Thyroid Carcinoma (MTC) is a neuroendocrine tumor originating from thyroid parafollicular cells, also called C cells, which secrete calcitonin. MTC accounts for 5% of thyroid cancers. Most cases of MTC are sporadic, and approximately 30% are associated with a hereditary syndrome called multiple endocrine neoplasia type 2 (MEN2A and MEN2B). In these syndromes, MTC is the most frequent tumor, comprising more than 95% of affected individuals. Distinct RET mutations are associated with both MEN2A and sporadic MTC. The RET oncogene encodes a tyrosine kinase receptor that while mutated causes constitutive activation of the MAPK pathway, important for regulating cell proliferation, thus resulting in the formation of tumors. Besides, over 70% of sporadic cases present somatic RET mutations in the tumor tissue. We speculate whether the extent of other oncogenes and tumor suppressor genes, such as BRAF and CKDN2A (p16) c-KIT and PI3KCA might also play a role as a second event. In fact, they are known to be involved in the tumorigenesis of other neural crest-derived tissues such as melanoma, pheochromocytoma, and paragangliomas, but little their role was studied in MTC. We believe that research in this direction can contribute to a better understanding of the progression of MTC with different behavior, and likely point to alternative therapeutic choices. Therefore, we propose to expand the evaluation of somatic mutations in the BRAF gene (codon 600), CKDN2A, c- KIT e PI3KCA as a somatic second event and correlate these molecular findings with the clinical outcome of patients who have been followed with MTC. (AU)