Wnt/beta-catenin pathway in pediatric adrenocortical tumors

• Grant number: 19/08041-4
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Effective date (Start): June 01, 2019
• Effective date (End): May 31, 2020
• Field of knowledge: Health Sciences - Medicine - Maternal and Child Health
• Principal Investigator: Sonir Roberto Rauber Antonini
• Grantee: Camila de Oliveira Toledo
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated research grant: 14/03989-6 - Uncovering pathophysiological and molecular mechanisms involved in tumorigenesis by platforms for next-generation sequencing (NGS), AP.TEM

Abstract

Background: Recent studies have increasingly demonstrated that adrenocortical tumorigenesis is a complex process that requires multiple molecular events and culminates in interactions between various intracellular signaling pathways. The Wnt / Beta-catenin signaling pathway regulates normal adrenal development and function and increasing clinical and scientific evidence has indicated its importance in adrenocortical tumorigenesis. This pathway appears to be activated in both adult adrenocortical tumors (CT) and pediatric CT. However, the mechanisms by which activation occurs appear to be different in these 2 groups of tumors. In a study that evaluated CT of Brazilian pediatric patients, mutations in the CTNNB1 gene were investigated, which were found and correlated with a poor prognosis. However, studies with a larger sample size are still lacking to confirm this important correlation. In addition, in the last few years, studies using broad genomic sequencing (NGS), exomic and / or transcriptome have been carried out, which increase knowledge about genetic alterations and their temporal relationships in pediatric adrenocortical tumorigenesis. This knowledge is important because it explains the flaws of conventional chemotherapy and may in the future contribute to the development of better prognostic classification and more effective therapies for pediatric TACs. Objectives: To assess in depth and more comprehensively Wnt / Beta-catenin pathway abnormalities by assessing genetic abnormalities in the CTNNB1 (Beta-catenin) gene and the ZNRF3, APC, AXIN1 genes in pediatric CT in an extended cohort. In addition, to evaluate the association between mutations in CTNNB1 and the tumor behavior and clinical outcome and the correlation of total and activated Beta-catenin labeling with the genetic abnormalities found. Individuals, Materials and Methods: Data from NGS study of 72 pediatric adrenocortical tumors will be analyzed. We will perform exomeric sequencing, transcriptome and qPCR validation of genes related to Wnt / Beta-catenin pathway. In addition, the protein expression will be assessed by means of immunohistochemistry with labeling for total and activated Beta-catenin. We will verify the existence of an association between clinical and pathological data with the results of genomic and transcriptomic analysis.