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Molecular, genomic, and computational approaches for reclassifying variants of uncertain clinical significance in hereditary cancer predisposing genes

Grant number: 22/05162-8
Support Opportunities:Regular Research Grants
Duration: April 01, 2023 - March 31, 2026
Field of knowledge:Biological Sciences - Genetics - Human and Medical Genetics
Principal Investigator:Giovana Tardin Torrezan
Grantee:Giovana Tardin Torrezan
Host Institution: A C Camargo Cancer Center. Fundação Antonio Prudente (FAP). São Paulo , SP, Brazil
Associated researchers:Dirce Maria Carraro ; Karina Miranda Santiago
Associated scholarship(s):23/18207-2 - Organization and sharing of genomic data, BP.TT


The genetic diagnosis of individuals at risk for hereditary cancer predisposition syndromes is performed through next-generation sequencing (NGS) of panels containing ten to hundreds cancer predisposition genes (CPGs). A significant part of genetic tests present uncertain results, with the identification of variants of unknown clinical significance (VUS), a finding that represents a major challenge for clinical practice. The application of advanced genomic methodologies, such as RNA target sequencing and exome sequencing to identify mutational signatures in tumors, have been shown to be effective in reclassifying VUS, since they can provide evidence of the transcriptional effect and functional impact of variants. Furthermore, the advances of in silico programs for predicting effects of non-coding variants (in intronic and untranslated regions - UTRs) enable the prioritization of variants that may have a regulatory role in transcription and translation and until now were deeply unexplored. The present study aims to establish genomic, computational and functional approaches aiming the reclassification of VUS in cancer predisposing genes. To this end, we will: establish criteria to identify and prioritize non-coding variants (intronic and in the 5' and 3' UTRs) or coding variants with possible splicing effects in previous genetic tests; validate a genetic test based on RNA target sequencing of 26 cancer predisposing genes; apply tumor exome sequencing of colorectal and endometrial tumors to assess mutational signatures of VUS in specific DNA repair genes. With this study we intend to establish a framework to improve the clinical interpretation of variants in CPGs, both in clinical diagnosis and translational research contexts, leading to more accurate diagnoses and positive impact on the management of cancer patients. (AU)

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