INVESTIGATION OF DPYD, MTHFR AND UGT1A1 GENES IN PATIENTS WHO DEVELOPED LETHAL TOXICITY TO 5-FLUOROURACIL IN NORTHERN BRAZIL

Introduction: Treatments based on fluoropyrimidines, represented by 5-fluorouracil (5-FU) and its oral prodrugs, have been widely used in several malignant cancer, including gastrointestinal cancer. However, more than 30% of patients develop severe toxicity and approximately 1% develop lethal toxicity. Identification of new polymorphisms in genes involved in the 5-FU metabolism pathway can contribute to the development of personalized treatment protocols, mainly applicable to mixed populations, such as the Brazilian one. The objective of this study was to analyze and describe the variants found in DPYD, MTHFR and UGT1A1 genes after investigating the exome in patients with gastric or colorectal cancer who died due to treatment with 5-FU. Methods: Biological samples (venous peripheral blood) were collected at reference services in oncology in Northern Brazil. Seven patients who developed fluoropyrimidine lethal toxicity were evaluated. Eighteen polymorphisms were selected based on their association with toxicities, clinical importance and new polymorphisms never described in the literature. Results: A total of 50 variants were identified in DPYD, MTHFR and UGT1A1 genes, seven variants are new, not previously described in the literature. Eleven polymorphisms found in these genes are related to enzyme deficiency, nine of them found in DPYD gene and one in each gene, MTHFR and UGT1A1. DPYD gene polymorphisms usually recommended as predictors of 5-FU toxicity by international regulatory agencies have not been observed in these patients. Conclusion: The Brazilian population is highly miscegenated and a large part of pharmacogenetic studies are performed in welldefined ethnic groups, so data from these groups may not be applied to most Brazilians. Therefore, knowing the molecular profile of the study population is essential to discover molecular biomarkers that can effectively identify patients at risk of severe toxicity, sometimes lethal toxicity, and enable greater safety and efficacy of treatment.