Functional analysis of MUTYH expression in monoallelic and biallelic contexts and its implication in the risk of cancer development

• Grant number: 19/00129-0
• Support Opportunities: Regular Research Grants
• Start date: October 01, 2019
• End date: September 30, 2022
• Field of knowledge: Biological Sciences - Genetics - Human and Medical Genetics
• Principal Investigator: Dirce Maria Carraro
• Grantee: Dirce Maria Carraro
• Host Institution: A C Camargo Cancer Center. Fundação Antonio Prudente (FAP). São Paulo , SP, Brazil

Abstract

DNA repair provides a major protection against cancer, and germline DNA repair defects in inherited syndromes confer a significant cancer predisposition. It has been shown that biallelic MUTYH mutations are associated with high increased risk of colorectal adenomas and cancer (CRC) compared with the general population, commonly known as MUTYH-associated polyposis (MAP). Moreover, biallelic MUTYH mutation carriers are also at increased risks of developing urinary bladder and ovarian cancers. However, monoallelic MUTYH mutations increase in more than nine times the risk to develop gastric tumor and in less intensity the risk of colorectal and breast cancer. Recently, mutational signatures captured from exome sequencing were associated with mutations in MUTYH. The MUTYH is a glycosylase involved in the base excision repair (BER) mechanism and is responsible to recognition and excision of an adenine mispared with oxidized guanine (8-oxoG) that was not repaired by the OGG1, another glycosylase involved in the repair of this modified base. The action of MUTYH is important to give time to OGG1 repair lesions left behind avoiding GC to TA transition. The MUTYH mutational signature reflecting persistent 8-oxoG:A mismatches occurs frequently in the APC, KRAS, PIK3CA, FAT4, TP53, FAT1, AMER1, KDM6A, SMAD4 and SMAD2 genes that are associated with colorectal cancer. However, this mutational signature has not yet been described in monoallelic MUTYH mutation-bearing tumors, and the mechanisms involved in the increased risk of some tumors are still unknown. We aim with this project to develop functional assays in three different tumor cell lines (colorectal, gastric and breast) to understand if there is any signature in different tumors associated to mono or biallelic MUTYH mutations and if there is any distinct biological pathways acting in different tissues. (AU)