Exploring the relationship between retroelements and extrachromosomal DNA in carcinogenesis

• Grant number: 25/11174-7
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: November 01, 2025
• End date: October 31, 2028
• Field of knowledge: Biological Sciences - Genetics - Human and Medical Genetics
• Principal Investigator: Pedro Alexandre Favoretto Galante
• Grantee: Daniela Moreira Mombach
• Host Institution: Hospital Sírio-Libanês. Sociedade Beneficente de Senhoras (SBSHSL). São Paulo , SP, Brazil

Abstract

Extrachromosomal circular DNA (eccDNA) constitutes a heterogeneous class of double-stranded circular DNA molecules that remain functionally independent from the nuclear genome. These structures present in different sizes, exhibit autonomous replicative capacity, and, according to emerging evidence in the literature, perform functions in cellular processes. Despite their ubiquitous presence in diverse organisms and human tissues, including neoplasms, the molecular mechanisms underlying these eccDNAs remain substantially unexplored. Extrachromosomal DNA (ecDNA), a specific subclass of eccDNA, demonstrates consistent association with malignant cellular phenotypes, contributing to genomic instability and promoting intratumoral heterogeneity, for instance. Notably, ecDNA modulates oncogene expression through non-chromosomal gene amplification mechanisms, and can serve as prognostic biomarkers and therapeutic targets in oncology. In parallel, mobile genetic elements, including transposable elements (TEs) and retrocopies, emerge as critical mediators of carcinogenesis, catalyzing chromosomal rearrangements and altering, for example, transcriptional regulatory elements. Although the functional interface between ecDNAs and retroelements remains largely unexplored, preliminary evidence suggests that TEs incorporated into ecDNAs may modulate tumor progression through yet unelucidated mechanisms. Currently, systematic investigation of TE composition in ecDNAs and their correlation with the formation of these extrachromosomal structures has become technically feasible through the integration of multi-omics data and novel computational pipelines. The present project proposes a comprehensive and systematic characterization of functional interactions between ecDNAs and retroelements through an integrative computational approach and experimental validation. We will analyze six distinct tumor histological types (> 4,000 samples) from three independent cohorts, including adjacent normal tissue, primary tumor, and metastases. This strategy will enable: (i) detailed molecular characterization of ecDNA content; (ii) quantification of the association between ecDNA frequency and TE activity; and (iii) experimental validation of computational findings through orthogonal methodologies, ensuring analytical robustness and reproducibility of results. Our findings may provide new understanding of non-canonical mechanisms of genomic instability and neoplastic progression, with translational potential for the development of prognostic biomarkers and novel therapeutic targets in oncology. (AU)