Molecular and metabolic alterations in the malignant phenotype acquisition in pleomorphic adenoma: diagnostic implications and novel genetic alterations

Author(s)

Reydson Alcides de Lima Souza

• Document type: Doctoral Thesis
• Press: Piracicaba, SP.
• Institution: Universidade Estadual de Campinas (UNICAMP). Faculdade de Odontologia de Piracicaba (FOP)
• Defense date: 2024-12-16

Examining board members

Fernanda Viviane Mariano; Claúdia Malheiros Coutinho Camillo; Carla Isabelly Rodrigues Fernandes; Danyel Elias da Cruz Perez; Pablo Agustin Vargas

• Advisor: Fernanda Viviane Mariano

Abstract

Pleomorphic adenoma (PA) is the most common salivary gland tumor and is characterized by a variety of histologic patterns including epithelial, myoepithelial, and mesenchymal components. Although benign, PA has the potential for recurrence, metastasis, and malignant transformation to carcinoma ex pleomorphic adenoma (CXPA). The etiology of this transformation remains uncertain, but it is believed to result from the accumulation of genetic, protein, metabolic, and epigenetic alterations. This study, divided into four chapters, aims to analyze the histological, molecular, and metabolic features involved in the acquisition of the malignant phenotype by PA. The first chapter examines the diagnostic challenges of PAs with malignant or pseudomalignant features. The findings highlight the complexity of accurate diagnosis and emphasize the importance of a detailed and comprehensive analysis. The second chapter reviews the major molecular alterations in PLAG1 and HMGA2 that are associated with the acquisition of the malignant phenotype in PA, as these genes are frequent targets of mutations in the pathogenesis of both PA and CXPA. The third chapter describes the molecular profile of CXPA using advanced techniques such as next-generation sequencing and fluorescence in situ hybridization. It was found that cases of CXPA with myoepithelial differentiation generally have gene rearrangements and fusions, while those with epithelial differentiation are characterized by gene variants and amplifications. In addition, a novel fusion, HMGA2::LINC02389, was identified. In the fourth chapter, a metabolomic study of the PA-CXPA sequence revealed that alterations in lipid pathways, especially those related to fatty acids, appear to play a crucial role in the acquisition of the malignant phenotype in PA. In addition, genetic analysis identified a novel fusion, NTF3::ITPR2, in one case of CXPA. Taken together, the results of this study highlight the complexity of the mechanisms underlying the pathogenesis of these lesions. The findings provide new insights into the acquisition of the malignant phenotype in PA that can be translated into clinically applicable therapies for the treatment of patients affected by these lesions (AU)

• FAPESP's process: 20/08431-4 - METABOLOMIC PROFILING ANALYSIS IN THE MALIGNANT TRANSFORMATION OF PLEOMORPHIC ADENOMA
• Grantee: Reydson Alcides de Lima Souza
• Support Opportunities: Scholarships in Brazil - Doctorate