Frequency analysis of mutations in the promoter region of TERT gene in well-differentiated thyroid carcinoma in Brazilian population and its association with clinical-pathological factors of poor prognosis

• Grant number: 16/25127-1
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: March 01, 2017
• End date: December 31, 2019
• Field of knowledge: Biological Sciences - Genetics - Human and Medical Genetics
• Principal Investigator: Janete Maria Cerutti
• Grantee: Vitor Rodrigues da Costa
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil

Abstract

The most common endocrine neoplasia is the well-differentiated thyroid carcinoma and its incidence has been increasing in the last years. Inside this group is included the papillary thyroid carcinoma (PTC), which represents the majority of the thyroid carcinomas. Usually, these PTC are non-aggressive, but there is a small group of this neoplasia that possesses a more aggressive fenotype. The main signaling pathway that is activated in a constitutive way is the MAPK pathway, and the most common mutation in PTC is BRAF V600E.Although this alteration has been proposed to be a marker of poor prognosis for being related to a more aggressive behavior of this tumor type, its high frequency (about 50%) makes it unfeasible to be used as a marker. Recently, another two mutations have been strongly associated to poor prognosis characteristics, bigger recurrence rates and mortality, being present in about 12% of PTC cases. Those mutations occur in the promoter region of the gene TERT, and both are the result of a transition between a cytosine and a thymine in the positions -124 C>T (C228T) and -146 C>T (C250T), in relation to the beginning of transcription of the gene, which creates new ligation sites of ETS transcription factors. Interestingly, when there is co-occurrence of the BRAF V600E mutation and mutation in the TERT promoter region, there is a synergy, and the cancer profile turns out to be more aggressive than with exclusive mutations. Differently from other more prevalent alterations found in PTCs, there is no data in the literature describing the prevalence in Brazil and the function of these mutations in TERT promoter region. In addition, no group in the world analyzed the prevalence of this mutation in PTC metastasis. Therefore, this project has the objective of evaluating the prevalence of those mutations in TERT promoter region, correlate it with different clinical-pathological factors of poor prognosis and the presence of the V600E mutation in BRAF and also to evaluate the prevalence those mutations in paired PTC metastasis. (AU)