A comprehensive study of novel Alu insertions in cancer.

• Grant number: 17/23575-0
• Support type: Scholarships abroad - Research Internship - Doctorate
• Effective date (Start): February 01, 2018
• Effective date (End): December 31, 2018
• Field of knowledge: Biological Sciences - Biochemistry - Molecular Biology
• Principal researcher: Pedro Alexandre Favoretto Galante
• Grantee: Fernanda Orpinelli Ramos do Rego
• Supervisor abroad: Kathleen Helen Burns
• Home Institution: Hospital Sírio-Libanês. Sociedade Beneficente de Senhoras (SBSHSL). São Paulo , SP, Brazil
• Research place: Johns Hopkins University (JHU), United States
• Associated to the scholarship: 15/25020-0 - Retroelements in primary and metastatic colorectal tumors., BP.DR

Abstract

Transposable elements were discovered in the 1940s, but their importance in genome composition, evolution and its role as regulatory elements occurred after the development of DNA sequencing methodologies. Those elements can be subdivided in two classes, DNA-transposons and retrotransposons, being the latter our focus of interest. Retrotransposition process is mediated by an enzymatic machinery called retrotransposase and it is provided by the most frequent element in human genome, LINE (Long Nuclear Interspersed Element). LINEs, specially LINE-1, are self-propagating, protein-coding retrotransposons that can use its own machinery to retrocopiate itself or other elements, as SINEs and retrocopies of coding genes, both non-autonomous elements. Alu, the most frequent family of SINEs, comprise 11% of the human genome and, although their intense activity in primate evolution, these elements continue to insert in modern humans causing copy number variation and diseases. Some authors recently showed that retroelements can be valuable markers of tumoral heterogeneity and clonal evolution, and they can be functionally important in revealing their activity in normal and precancerous tissues. We believe that retroelements, specially the underexploited Alus, may play an important role in tumorigenesis and the improvement of methods to identify insertion points of those elements will led fundamental advances in understanding their impact in cancer biology. Here, we propose a study of novel Alu sequence insertions in tumor and normal tissues based on the TIPseq methodology. We intend to explore the role of the somatically acquired insertions in the context of carcinogenesis exploring a novel approach to map retroelements using genomic DNA from cell lines, normal and tumor samples. In the end, we expect to understand the frequency, the impacts and the importance of these events during tumor evolution and their contribution to intratumoral heterogeneity.