Mutation signatures in hepatoblastoma and effect of nitrosamine exposure on hepatic tumorigenesis in children

• Grant number: 23/17465-8
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: April 01, 2024
• End date: August 31, 2027
• Field of knowledge: Biological Sciences - Genetics - Human and Medical Genetics
• Principal Investigator: Ana Cristina Victorino Krepischi
• Grantee: Gustavo Dib Dangoni
• Host Institution: Instituto de Biociências (IB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

The identification of mutational signatures patterns in the tumor genome provides crucial data for the genetic landscape of cancer, in addition to the detection of potential endogenous and environmental factors associated with tumorigenesis. Previously, our research group identified in hepatoblastomas (HBs) an enrichment of the COSMIC signature SBS29, known to be derived from tobacco. Exposure during pregnancy to N-nitrous compounds originated from tobacco derived nicotine and other sources was previously related to prematurity and low birth weight, which are significant risk factors of HBs. Our hypothesis is that the exposure of undifferentiated liver cells from the fetus to N-nitrous compounds contributes to the development of HBs, generating specific mutational signatures. To test the hypothesis of the project, we propose two objectives: (a) expansion of the mutational signature project in a new group of HBs (whole genome sequencing of paired tumor/germline samples), to validate the occurrence of the SBS29 signature and investigate mutational signatures recently described in cancer and never investigated in HBs (doublet base substitutions, indel, copy number variations, structural variations and RNA single base substitution signatures); and (b) implementation of an experimental in vitro model from human hepatic cells to investigate the etiological association among the environmental exposure (nitrosamines), generation of a specific mutational signature, and activation of related biological pathways, investigated by transcriptome analysis (RNASeq). The results of new mutational signatures in HBs and the possible effect of nitrosamine exposure on human hepatic cells will generate novel data, contributing with an input of experimental data, which may support the hypothesis that exposure to these carcinogens in the embryonic period could be a risk factor for the development of HBs.