PFKFB2 Promoter Hypomethylation as Recurrence Predictive Marker in Well-Differentiated Thyroid Carcinomas

Author(s)

Barros-Filho, Mateus Camargo ^[1] ; Menezes de Lima, Larissa Barreto ^[1] ; dos Reis, Mariana Bisarro ^[1] ; Homem de Mello, Julia Bette ^[1] ; Beltrami, Caroline Moraes ^[1] ; Lopes Pinto, Clovis Antonio ^[2] ; Kowalski, Luiz Paulo ^[3] ; Rogatto, Silvia Regina ^[4]

Affiliation

^[1] AC Camargo Canc Ctr, Int Res Ctr CIPE, BR-01508010 Sao Paulo - Brazil

^[2] AC Camargo Canc Ctr, Dept Pathol, BR-01509900 Sao Paulo - Brazil

^[3] AC Camargo Canc Ctr, Dept Head & Neck Surg & Otorhinolaryngol, BR-01509900 Sao Paulo - Brazil

^[4] Univ Southern Denmark, Dept Clin Genet, Vejle Hosp, Inst Reg Hlth Res, DK-7100 Vejle - Denmark

• Document type: Journal article
• Source: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES; v. 20, n. 6 MAR 16 2019.
• Web of Science Citations: 3

Abstract

Despite the low mortality rates, well-differentiated thyroid carcinomas (WDTC) frequently relapse. BRAF and TERT mutations have been extensively related to prognosis in thyroid cancer. In this study, the methylation levels of selected CpGs (5-cytosine-phosphate-guanine-3) comprising a classifier, previously reported by our group, were assessed in combination with BRAF and TERT mutations. We evaluated 121 WDTC, three poorly-differentiated/anaplastic thyroid carcinomas (PDTC/ATC), 22 benign thyroid lesions (BTL), and 13 non-neoplastic thyroid (NT) tissues. BRAF (V600E) and TERT promoter (C228T and C250T) mutations were tested by pyrosequencing and Sanger sequencing, respectively. Three CpGs mapped in PFKFB2, ATP6V0C, and CXXC5 were evaluated by bisulfite pyrosequencing. ATP6V0C hypermethylation and PFKFB2 hypomethylation were detected in poor-prognosis (PDTC/ATC and relapsed WDTC) compared with good-prognosis (no relapsed WDTC) and non-malignant cases (NT/BTL). CXXC5 was hypomethylated in both poor and good-prognosis cases. Shorter disease-free survival was observed in WDTC patients presenting lower PFKFB2 methylation levels (p = 0.004). No association was observed on comparing BRAF (60.7%) and TERT (3.4%) mutations and prognosis. Lower PFKFB2 methylation levels was an independent factor of high relapse risk (Hazard Ratio = 3.2; CI95% = 1.1-9.5). PFKFB2 promoter methylation analysis has potential applicability to better stratify WDTC patients according to the recurrence risk, independently of BRAF and TERT mutations. (AU)

• FAPESP's process: 15/17707-5 - Development of molecular procedures useful for differential diagnosis in thyroid nodules
• Grantee: Mateus de Camargo Barros Filho
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 15/20748-5 - Diagnostic and prognostic markers useful in the clinical practice for patients with thyroid nodules: validation of previous findings and functional studies
• Grantee: Silvia Regina Rogatto
• Support Opportunities: Regular Research Grants