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Ana Carolina Bueno, Aniette R Espiñeira, Fábio L Fernandes-Rosa, Roberto Molina de Souza, Margaret de Castro, Ayrton Custódio Moreira, Heloísa Bettiol, Marco Antonio Barbieri, and Sonir R Antonini

Objective

To assess whether the −11391G>A polymorphism in the regulatory region of the adiponectin gene (ADIPOQ) is associated with birth size, postnatal growth, adiponectinemia, and cardiometabolic risk in adult life.

Design

Case–control study nested within a prospective cohort of 2063 community subjects born in 1978/1979 and followed since birth to date.

Methods

ADIPOQ −11391G>A genotype–phenotype associations were evaluated in 116 subjects born large for gestational age (LGA) and 392 gender-matched controls at birth (birth size), at 8–10 years (catch-down growth), and at 23–25 years of age (cardiometabolic profile).

Results

The −11391A variant allele frequency was higher in LGA subjects (P=0.04). AA genotype was associated with augmented probability of being born LGA (odds ratio=4.14; 95% confidence interval: 1.16–16.7; P=0.03). This polymorphism was associated neither with body composition nor with postnatal growth pattern. At the age of 23–25 years, the −11391A variant allele was associated with higher serum adiponectin levels (GG: 10.7±6.2 versus GA: 12.2±6.5 versus AA: 14.2±6.8 μg/ml; P<0.01). Subjects born LGA presented higher body mass index (BMI; P=0.01), abdominal circumference (P=0.04), blood pressure (P=0.04), and homeostasis assessment model for insulin resistance (P=0.01) than adequate for gestational age. Symmetry at birth did not influence these variables. The occurrence of catch-down of weight was associated with lower BMI and abdominal circumference (P<0.001) at 23–25 years.

Conclusions

The −11391A ADIPOQ gene variant was associated with increased chance of being born LGA and with higher adiponectin levels in early adult life.

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Jose Italo Soares Mota, Rui Milton Patrício Silva-Júnior, Clarissa Silva Martins, Ana Carolina Bueno, Luiz Eduardo Wildemberg, Ximene Lima da Silva Antunes, Jorge Guilherme Okanobo Ozaki, Fernanda Borchers Coeli-Lacchini, Carlos Garcia-Peral, Antonio Edson Rocha Oliveira, Antônio Carlos Santos, Ayrton Custodio Moreira, Helio Rubens Machado, Marcelo Volpon dos Santos, Leandro M Colli, Monica R Gadelha, Sonir Roberto R Antonini, and Margaret de Castro

Objectives

To evaluate how telomere length behaves in adamantinomtous craniopharyngioma (aCP) and if it contributes to the pathogenesis of aCPs with and without CTNNB1 mutations.

Design

Retrospective cross-sectional study enrolling 42 aCP patients from 2 tertiary institutions.

Methods

Clinicopathological features were retrieved from the patient’s charts. Fresh frozen tumors were used for RNA and DNA analyses. Telomere length was evaluated by qPCR (T/S ratio). Somatic mutations in TERT promoter (TERTp) and CTNNB1 were detected by Sanger and/or whole-exome sequencing. We performed RNA-Seq to identify differentially expressed genes in aCPs presenting with shorter or longer telomere lengths.

Results

Mutations in CTNNB1 were detected in 29 (69%) tumors. There was higher frequency of CTNNB1 mutations in aCPs from patients diagnosed under the age of 15 years (85% vs 15%; P = 0.04) and a trend to recurrent disease (76% vs 24%; P = 0.1). No mutation was detected in the TERTp region. The telomeres were shorter in CTNNB1-mutated aCPs (0.441, IQR: 0.297–0.597vs 0.607, IQR: 0.445–0.778; P = 0.04), but it was neither associated with clinicopathological features nor with recurrence. RNAseq identified a total of 387 differentially expressed genes, generating two clusters, being one enriched for short telomeres and CTNNB1-mutated aCPs.

Conclusions: CTNNB1

mutations are more frequent in children and adolescents and appear to associate with progressive disease. CTNNB1-mutated aCPs have shorter telomeres, demonstrating a relationship between the Wnt/β-catenin pathway and telomere biology in the pathogenesis of aCPs.

Restricted access

Ana Carolina Bueno, Mônica F Stecchini, Junier Marrero-Gutiérrez, Candy Bellido More, Leticia Ferro Leal, Débora Cristiane Gomes, Daniel Ferreira de Lima Neto, Silvia Regina Brandalise, Izilda Aparecida Cardinalli, José Andres Yunes, Thais Junqueira, Carlos Alberto Scrideli, Carlos Augusto Fernandes Molina, Fernando Silva Ramalho, Silvio Tucci, Fernanda Borchers Coeli-Lacchini, Ayrton Custodio Moreira, Leandra Ramalho, Ricardo Zorzetto Nicoliello Vêncio, Margaret De Castro, and Sonir Roberto R Antonini

Objective

Pediatric adrenocortical tumors (pACT) display complex genomic backgrounds, lacking robust prognostic markers and targeted therapeutic options. Vitamin D3 receptor (VDR) promoter hypermethylation and underexpression were reported in adrenocortical carcinomas from adult patients. In this study, we aimed to investigate VDR expression levels and methylation status in pACT and their clinical and prognostic significance.

Design

Retrospective cross-sectional study enrolling pediatric patients with ACT from two tertiary referral institutions.

Methods

We evaluated clinicopathological features, VDR mRNA (qPCR) and protein (immunohistochemistry) expression, and VDR-wide methylation of ACT samples from 108 pediatric patients. Fourteen pediatric and 32 fetal and postnatal normal adrenals were used as controls.

Results

Unlike in pre- and post-natal normal adrenals, most pACT lacked nuclear VDR expression and had reduced mRNA levels, especially the carcinomas. Unsupervised analysis of VDR methylation data revealed two groups of pACT with distinct disease features and outcomes. Tumors with high VDR methylation presented lower mRNA levels, and the respective patients presented advanced disease and reduced disease-free and overall survival.

Conclusions

VDR has a role in normal adrenocortical development and homeostasis, which is impaired during tumorigenesis. VDR hypermethylation and underexpression may be both predictive and prognostic biomarkers for pACT.