• JoomlaWorks Simple Image Rotator
  • JoomlaWorks Simple Image Rotator
  • JoomlaWorks Simple Image Rotator
  • JoomlaWorks Simple Image Rotator
  • JoomlaWorks Simple Image Rotator
  • JoomlaWorks Simple Image Rotator
  • JoomlaWorks Simple Image Rotator
  • JoomlaWorks Simple Image Rotator
  • JoomlaWorks Simple Image Rotator
  • JoomlaWorks Simple Image Rotator
 
  Bookmark and Share
 
 
Doctoral Thesis
DOI
https://doi.org/10.11606/T.17.2022.tde-06022023-112309
Document
Author
Full name
Mônica Freire Stecchini
Institute/School/College
Knowledge Area
Date of Defense
Published
Ribeirão Preto, 2022
Supervisor
Committee
Antonini, Sonir Roberto Rauber (President)
Lerário, Antonio Marcondes
Reis, Rui Manuel Vieira
Valera, Elvis Terci
Title in Portuguese
Avaliação do papel dos genes ATRX e DAXX na patogênese e no prognóstico de tumores adrenocorticais pediátricos
Keywords in Portuguese
ATRX
DAXX
Telômeros
Tumor adrenocortical pediátrico
Abstract in Portuguese
Contexto: O conhecimento sobre a patogênese dos tumores adrenocorticais (TAC) em pacientes pediátricos ainda é incompleto. Alterações nos fatores de remodelamento da cromatina ATRX e DAXX tem sido reconhecidas como elementos importantes para a tumorigênese e para a avaliação prognóstica de diferentes tipos de câncer. Seu papel em TAC pediátricos ainda requer maior investigação e confirmação. Objetivo: Avaliar a expressão dos genes ATRX e DAXX, a expressão das proteínas ATRX e DAXX, o comprimento telemétrico e o alongamento alternativo dos telômeros (ALT), bem como sua significância clínica, em amostras de TAC primários de pacientes pediátricos. Métodos: A expressão dos genes ATRX, DAXX, TERT e TERC foi avaliada por qPCR; a expressão das proteínas ATRX e DAXX, por IHC; o comprimento telemétrico, por qPCR; e o ALT, por FISH. Para análise de sobrevida, curvas de Kaplan-Meier foram construídas. Para análise de correlação, o coeficiente de Spearman foi utilizado. Resultados: A maioria dos 106 pacientes era do sexo feminino (71,7%) e era portadora da variante germinativa TP53 p.R337H (84,9%). A mediana de idade ao diagnóstico foi de 22,1 meses. Idade ao diagnóstico inferior a quarto anos foi associada a melhor prognóstico, enquanto doença avançada e classificação como carcinoma pelo escore de Wieneke foram associadas a pior prognóstico. A expressão do gene ATRX foi diminuída (p < 0,01), enquanto a expressão do gene DAXX foi aumentada em TAC (p < 0,01). A expressão da proteína ATRX foi perdida na maioria das amostras (95,6%), enquanto a expressão da proteína DAXX, na minoria (22,2%). Houve correlação negativa fraca entre a expressão dos genes ATRX (ρ = -0,35; p = 0,008) e DAXX (ρ = -0,3; p = 0,023) e o comprimento telemétrico. ALT estava presente em 27,3% dos TAC. Não houve associação entre expressão genica / proteica, comprimento telemétrico ou ALT e a sobrevida livre de doença ou total. Conclusão: Os resultados deste estudo demonstram que alterações na expressão dos genes ATRX e DAXX, bem como na expressão das proteínas ATRX e DAXX, ocorrem em TAC de pacientes pediátricos e tem influencia sobre o comprimento dos telômeros, porém sem associação com o prognóstico desses pacientes.
Title in English
Evaluation of the role of ATRX and DAXX genes in the pathogenesis and prognosis of pediatric adrenocortical tumors
Keywords in English
ATRX
DAXX
Pediatric adrenocortical tumor
Telomeres
Abstract in English
Context: The knowledge of the pathogenesis of adrenocortical tumors (ACT) in pediatric patients is still incomplete. Alterations in the chromatin remodeling factors ATRX and DAXX have been recognized as important elements for tumorigenesis and prognostic evaluation in different types of cancer. Their role in pediatric ACT still requires further investigation and confirmation. Purpose: To evaluate ATRX and DAXX gene expression, ATRX and DAXX protein expression, telomere length and the alternative lengthening of telomeres (ALT), as well as their clinical significance, in primary ACT samples from pediatric patients. Methods: ATRX, DAXX, TERT and TERC gene expression was assessed by qPCR. ATRX and DAXX protein expression was assessed by IHC. Telomere length was assessed by qPCR. ALT was assessed by FISH. For survival analysis, Kaplan- Meier curves were obtained. For correlation analysis, Spearman coefficient was used. Results: Most of the 106 patients were female (71.7%) and harbored the TP53 p.R337H germline variant (84.9%). Median age at diagnosis was 22.1 months. Age at diagnosis below four years was associated with better prognosis, while advanced disease and classification as carcinoma by the Wieneke score were associated with worse prognosis. ATRX gene expression was decreased (p < 0.01), while DAXX gene expression was increased (p < 0.01) in ACT. ATRX protein expression was lost in most samples (95.6%), while DAXX was lost in a minority (22.2%). There was a weak negative correlation between ATRX (ρ = -0,35; p = 0,008) and DAXX (ρ = -0,3; p = 0,023) gene expression and telomere length. ALT was present in 27.3% of ACT. There was no association between gene / protein expression, telomere length or ALT and disease-free or overall survival. Conclusion: The results of this study show that alterations in ATRX and DAXX gene expression, as well as in ATRX and DAXX protein expression, occur in ACT from pediatric patients, and influence telomere length, but without association with the prognosis of these patients.
 
WARNING - Viewing this document is conditioned on your acceptance of the following terms of use:
This document is only for private use for research and teaching activities. Reproduction for commercial use is forbidden. This rights cover the whole data about this document as well as its contents. Any uses or copies of this document in whole or in part must include the author's name.
Publishing Date
2023-02-08
 
WARNING: Learn what derived works are clicking here.
All rights of the thesis/dissertation are from the authors
CeTI-SC/STI
Digital Library of Theses and Dissertations of USP. Copyright © 2001-2024. All rights reserved.