Dados do Trabalho


Whole exome sequencing reveals key oncogenes and tumor suppressor genes driving the carcinoma ex pleomorphic adenoma development


Among tumors that can affect salivary glands, two provide an interesting model for studying malignant transformation mechanisms. The first is Pleomorphic Adenoma (PA), which is the most common benign tumor in salivary glands. PA has the potential to undergo genetic changes that lead to its malignant counterpart, Carcinoma Ex-Pleomorphic Adenoma (CXPA). CXPA is a rare and aggressive malignant neoplasm of the salivary glands that exhibits distinct biological behavior and prognosis. The development of CXPA may be driven by genetic alterations, including oncogene activation and tumor suppressor gene inactivation. The lack of genetic characterization and limited access to research tools for rare cancers pose significant challenges in enhancing our understanding of these diseases, including CXPA.


To identify the genetic alterations that drive the development of CXPA using whole exome-sequencing (WES).


Ethical approval for this study was obtained from CEP-UNICAMP (#2.115.019), CEP-Hospital AC Camargo Cancer Center (#2.485.588), and CEP-FOP/UNICAMP (#2.928.348). WES was performed on DNA samples from 13 CXPA cases, with sequencing reads aligned to the hg38 reference genome. Single nucleotide variants (SNVs) were identified in all samples, and a population disease allele frequency (AF) ≥0.2 filter was applied to the data. Genes available in the Tumor Suppressor Genes ( and Oncogene ( databases were used for comparison. To determine the most likely biological effects of the mutated genes, gene ontology (GO) analysis (p<0.05) was performed on this WES data. The mutated genes in each group were classified into different functional categories based on the GO term enrichment analysis.


In the database containing 1060 Tumor Suppressor Genes, our cohort encompassed 1.5% (16): PCDH9, LRMP, KDM5A, BHLHE41, EPB41L3, RB1, NEDD4L, ARG1, SMYD4, CNDP2, CHFR, TP53, PTPRT, ARL11, STARD13, SEPTIN4. Among the 789 oncogenes within the database, 0.9% (7) emerged in CXPA: SLC12A5, IRS2, LHX1, INPPL1, MYB, CD24, SATB1. Our analysis of shared oncogenes and tumor suppressor genes across the three groups yielded the top ten functional enrichment results. These prominently pointed to the negative regulation of cell communication and signaling. Additionally, the enriched KEGG pathways underscored the significance of the insulin signaling pathway, colorectal cancer pathway, and MAPK signaling pathway (including TP53, BRAF, MAP2K4, and NF1 mutations) .


The findings suggest a sequential progression from PA to CXPA, driven by the activation of multiple oncogenes and the inactivation of tumor suppressor genes. These findings provide critical insights into the underlying molecular mechanisms of these tumors. Notably, the presence of point mutations in the MYB gene was identified for the first time in the PA-CXPA sequence. This breakthrough introduces potential avenues for the development of targeted therapies, opening new possibilities for effectively combating this tumor.


Whole Exome Sequencing; Pleomorphic Adenoma; Carcinoma Ex Pleomorphic Adenoma

Financiador do resumo

This work was supported by the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP, grant numbers 15/07304-0, 19/09419-0, and 21/12567-1). We thank the Brazilian Initiative on Precision Medicine (BIPMed) for allowing us to use anonymous raw data from its public database.


Estudo Clínico - Tumores de Cabeça e Pescoço


JOAO FIGUEIRA SCARINI, Sheila Tiemi Nagamatsu, Luciana Souto Mofatto, Marcelo Falsarella Carazzolle, Rodrigo Maioral, Erika Said Abu Egal, Cristiane Squarize, Rogerio Castilho, Albina Altemani, Fernanda Viviane Mariano