INFLUENCE OF ANCESTRY ON THE FREQUENCY OF GENETIC VARIANTS IN GENES RELATED TO METABOLISM AND TRANSPORT OF ANTINEOPLASTIC DRUGS IN THE BRAZILIAN POPULATION SERVED IN THE BRAZILIAN UNIFIED HEALTH SYSTEM

• Grant number: 25/00059-2
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Start date: June 01, 2025
• End date: February 28, 2029
• Field of knowledge: Health Sciences - Pharmacy
• Principal Investigator: Patricia Moriel
• Grantee: Julia Tiemi Siguemoto
• Host Institution: Faculdade de Ciências Farmacêuticas (FCF). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil

Abstract

Pharmacogenetics is fundamental in the personalization of oncological therapy, enabling greater efficacy and safety by identifying genetic variants that influence the response to antineoplastic agents. The Brazilian population, characterized by its extensive admixture among Europeans, Africans, and Amerindians, exhibits genetic diversity that significantly impacts the frequencies of pharmacogenomic variants. International studies, predominantly based on European populations, may not accurately reflect the genetic characteristics of mixed populations, such as the Brazilian one, limiting the applicability of global clinical guidelines. The correlation of these variants with genetic ancestry, clinical, and demographic parameters provides the basis for developing specific pharmacogenetic guidelines, promoting more inclusive and effective personalized medicine for cancer treatment. Incorporating these findings can optimize oncological treatments and minimize adverse effects, aligning with the needs of Brazil's genetic diversity. Thus, the project's aim is to study how ancestry relates to the frequency of genetic variants in genes associated with the metabolism and transport of antineoplastic agents in the Brazilian population treated by the Unified Health System (SUS). To achieve this, a retrospective cohort study (n = 900) will be conducted with patients diagnosed with gynecological, lung, or head and neck cancer at any clinical stage. Data related to these patients' clinical histories will be collected. Additionally, genomic DNA will be extracted from leukocytes in previously collected peripheral blood. The purity of the extracted DNA will be evaluated using the QuantiFluor® dsDNA System (Promega), and concentrations will be diluted with PCR-grade water for subsequent genotyping. The investigation of single nucleotide variants (SNVs) will be conducted using the Infinium Global Diversity Array with Enhanced PGx (GDA PGx; Illumina) on the iScan platform (Illumina). For ancestry analysis, a machine learning model from the company, which uses Maximum Likelihood Estimation to estimate ancestry proportions based on the genetic profile of the samples and allele frequencies of thousands of single nucleotide variants, will be applied. Descriptive analysis will be performed, presenting absolute/percentage frequencies for categorical variables and measures of central tendency (mean, median) and dispersion (standard deviation, range) for numerical variables. Hardy-Weinberg equilibrium will be tested for all studied SNPs. Different genotypes for each genetic variant will be used to form groups. A significance level of 5% (p < 0.05) will be adopted in all analyses.