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

Mateus Camargo Barros-Filho, Larissa Barreto Menezes de Lima, Mariana Bisarro Dos Reis, Julia Bette Homem de Mello, Caroline Moraes Beltrami, Clóvis Antonio Lopes Pinto, Luiz Paulo Kowalski, Silvia Regina Rogatto*

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Resumé

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.

OriginalsprogEngelsk
Artikelnummer1334
TidsskriftInternational Journal of Molecular Sciences
Vol/bind20
Udgave nummer6
Antal sider13
ISSN1661-6596
DOI
StatusUdgivet - 16. mar. 2019

Fingeraftryk

Methylation
markers
cancer
prognosis
mutations
methylation
Cytosine
Guanine
Mutation
Phosphates
guanines
lesions
Hazards
phosphates
Classifiers
Association reactions
Tissue
sequencing
mortality
Disease-Free Survival

Citer dette

Camargo Barros-Filho, M., Barreto Menezes de Lima, L., Bisarro Dos Reis, M., Bette Homem de Mello, J., Moraes Beltrami, C., Lopes Pinto, C. A., ... Rogatto, S. R. (2019). PFKFB2 Promoter Hypomethylation as Recurrence Predictive Marker in Well-Differentiated Thyroid Carcinomas. International Journal of Molecular Sciences , 20(6), [1334]. https://doi.org/10.3390/ijms20061334
Camargo Barros-Filho, Mateus ; Barreto Menezes de Lima, Larissa ; Bisarro Dos Reis, Mariana ; Bette Homem de Mello, Julia ; Moraes Beltrami, Caroline ; Lopes Pinto, Clóvis Antonio ; Kowalski, Luiz Paulo ; Rogatto, Silvia Regina. / PFKFB2 Promoter Hypomethylation as Recurrence Predictive Marker in Well-Differentiated Thyroid Carcinomas. I: International Journal of Molecular Sciences . 2019 ; Bind 20, Nr. 6.
@article{00dc100c5773479b9983546f09d693b5,
title = "PFKFB2 Promoter Hypomethylation as Recurrence Predictive Marker in Well-Differentiated Thyroid Carcinomas",
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.",
keywords = "BRAF mutation, DNA methylation, PFKFB2, prognosis, TERT promoter mutation, well-differentiated thyroid carcinoma, Well-differentiated thyroid carcinoma, Prognosis",
author = "{Camargo Barros-Filho}, Mateus and {Barreto Menezes de Lima}, Larissa and {Bisarro Dos Reis}, Mariana and {Bette Homem de Mello}, Julia and {Moraes Beltrami}, Caroline and {Lopes Pinto}, {Cl{\'o}vis Antonio} and Kowalski, {Luiz Paulo} and Rogatto, {Silvia Regina}",
year = "2019",
month = "3",
day = "16",
doi = "10.3390/ijms20061334",
language = "English",
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journal = "International Journal of Molecular Sciences",
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Camargo Barros-Filho, M, Barreto Menezes de Lima, L, Bisarro Dos Reis, M, Bette Homem de Mello, J, Moraes Beltrami, C, Lopes Pinto, CA, Kowalski, LP & Rogatto, SR 2019, 'PFKFB2 Promoter Hypomethylation as Recurrence Predictive Marker in Well-Differentiated Thyroid Carcinomas', International Journal of Molecular Sciences , bind 20, nr. 6, 1334. https://doi.org/10.3390/ijms20061334

PFKFB2 Promoter Hypomethylation as Recurrence Predictive Marker in Well-Differentiated Thyroid Carcinomas. / Camargo Barros-Filho, Mateus; Barreto Menezes de Lima, Larissa; Bisarro Dos Reis, Mariana; Bette Homem de Mello, Julia; Moraes Beltrami, Caroline; Lopes Pinto, Clóvis Antonio; Kowalski, Luiz Paulo; Rogatto, Silvia Regina.

I: International Journal of Molecular Sciences , Bind 20, Nr. 6, 1334, 16.03.2019.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - PFKFB2 Promoter Hypomethylation as Recurrence Predictive Marker in Well-Differentiated Thyroid Carcinomas

AU - Camargo Barros-Filho, Mateus

AU - Barreto Menezes de Lima, Larissa

AU - Bisarro Dos Reis, Mariana

AU - Bette Homem de Mello, Julia

AU - Moraes Beltrami, Caroline

AU - Lopes Pinto, Clóvis Antonio

AU - Kowalski, Luiz Paulo

AU - Rogatto, Silvia Regina

PY - 2019/3/16

Y1 - 2019/3/16

N2 - 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.

AB - 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.

KW - BRAF mutation

KW - DNA methylation

KW - PFKFB2

KW - prognosis

KW - TERT promoter mutation

KW - well-differentiated thyroid carcinoma

KW - Well-differentiated thyroid carcinoma

KW - Prognosis

U2 - 10.3390/ijms20061334

DO - 10.3390/ijms20061334

M3 - Journal article

C2 - 30884810

AN - SCOPUS:85063300278

VL - 20

JO - International Journal of Molecular Sciences

JF - International Journal of Molecular Sciences

SN - 1661-6596

IS - 6

M1 - 1334

ER -

Camargo Barros-Filho M, Barreto Menezes de Lima L, Bisarro Dos Reis M, Bette Homem de Mello J, Moraes Beltrami C, Lopes Pinto CA et al. PFKFB2 Promoter Hypomethylation as Recurrence Predictive Marker in Well-Differentiated Thyroid Carcinomas. International Journal of Molecular Sciences . 2019 mar 16;20(6). 1334. https://doi.org/10.3390/ijms20061334