Integration of genomic and microbiome data in investigating the mechanisms involved in penile cancer development

• Ano de defesa: 2025
• Autor(a) principal: Júnior, Antonio Augusto Lima Teixeira
• Tipo de documento: Tese
• Tipo de acesso: Acesso aberto
• Idioma: eng
• Instituição de defesa: Biblioteca Digitais de Teses e Dissertações da USP
• Palavras-chave em Português: Câncer de pênis; Exoma; Exome; Lymph node metastasis; Metástase linfonodal; Microbioma; Microbiome; Penile squamous cell carcinoma; Transcriptoma; Transcriptome
• Link de acesso: https://www.teses.usp.br/teses/disponiveis/17/17135/tde-03092025-142014/

Penile squamous cell carcinoma (PSCC) is a rare and highly aggressive malignancy that remains underexplored, especially in high-incidence regions such as Brazil. This study aimed to integrate genomic, transcriptomic, and microbiome analyses to identify molecular signatures and potential biomarkers associated with PSCC progression, particularly its lymph node metastases. A prospective cohort of patients diagnosed with PSCC was established, from whom primary tumor (PT), metastatic lymph nodes (MT), and adjacent normal tissues were collected. Clinical, histopathological, and socio-economic data were recorded to correlate molecular findings with disease features. HPV detection and genotyping were performed to determine viral subtypes, physical state, and activity, revealing its potential role in PSCC etiology. Using Whole-Exome Sequencing (WES), recurrent mutations in TP53, KMT2D, and FAT1 were identified, along with APOBEC-related mutational signatures. Differential Variant Allele Frequency (VAF) analysis demonstrated the loss or persistence of specific mutations in metastatic samples, suggesting evolutionary dynamics in tumor progression. Tumor mutational burden (TMB) was also evaluated, with higher values observed in metastatic samples. RNA-seq analysis revealed differentially expressed genes (DEGs) between PT and MT, enriched in immune response, inflammation, and epithelial-mesenchymal transition (EMT) pathways. Gene Ontology (GO) and KEGG analyses highlighted pathways such as cytokine-cytokine receptor interactions, NF-kappa B signaling, and chemokine activity as key drivers of tumor metastasis. Microbiome profiling using 16S rRNA sequencing demonstrated significant bacterial dysbiosis in PSCC samples, with increased abundance of Escherichia-Shigella and other taxa in metastatic tissues. This dysbiosis may reflect microenvironmental changes that favor tumor progression. The present study integrates genomic, transcriptomic, and microbiome data to provide a comprehensive characterization of PSCC. The findings uncover key molecular pathways, HPV associations, and microbial alterations contributing to tumor development and metastasis. especially promoting an inflammatory microenvironment. These insights offer new insights for potential biomarkers to improve the current knowledge about PSCC molecular mechanism, especially those related to lymph node metastases.