Identification of pharmacogenomic variants associated with oncology treatments in Brazilian Amazonian Amerindians.
Authors: Rodrigues Juliana Carla Gomes , Fernades Marianne Rodrigues , Barra Williams Fernandes , Pereira Esdras Edgar Batista , Ribeiro-dos-Santos André , Assumpção Paulo Pimentel , Guerreiro João Farias , Ribeiro-dos-Santos Andrea , Santos Sidney Emanuel Batista dos , Santos Ney Pereira Carneiro dos 
Published: June 2022

e15082

Background: Adverse drug reactions are an important cause of morbidity and mortality commonly found in different therapeutic regimens, particularly in oncologic. About 20-30% of these reactions are due to the individual genetic variability of patients. Pharmacogenomics focuses on the identification of genetic variants that influence drug efficacy, response, and/or toxicity by changes in pharmacokinetics/pharmacodynamics. Pharmacogenomic investigations are known to have a population bias. There is a gap in the accumulated about pharmacogenomic variants in poorly studied populations, such as the Amerindian population from the Brazilian Amazon region. The objective of this work is to describe the pharmacogenetic variability regarding 160 pharmacogenes involved in pharmacokinetic processes and biological pathways of different therapies, including oncology treatments, based on data obtained through complete exome sequencing of 64 individuals from different Amerindian groups of the Brazilian Amazon. Methods: The present study was approved by the National Committee for Ethics in Research and the Research Ethics Committee of the UFPA Tropical Medicine Center, under CAAE number 20654313.6.0000.5172. All participants signed a free-informed consent. The DNA extraction was performed using phenol-chloroform. Libraries were prepared using the Nextera Rapid Capture Exome and SureSelect Human All Exon V6 kits. Bioinformatic analysis was performed by ViVa software. Results: Our results show a total of 3,311 variants found in the study subjects. Of this, 167 are exclusive variants found in the Amerindians. Among these new variants, we found a non-synonymous coding variant in the DPYD gene with an allelic frequency of 3%, and variants with high allelic frequencies in intronic regions, which may regulate gene expression: MTHFR (5.56%), TYMS (11.5%) GSTT1 (54.1%), and three variants in the CYP2D6 gene with frequencies of 54%, 62.3%, and 65.6%. The DPYD is a pivotal gene involved with the efficacy of fluoropyrimidine-based treatment; the MTHFR and TYMS genes also participate in the biological pathways of these drugs, responsible for variation in response rates. The GSTT1 is a gene associated with platinum-based treatments, such as carboplatin and cisplatin. And, finally, CYP2D6 is one of the main pharmacogene described, involved in several drug schemes, including tamoxifen and gefitinib, used to treat breast and lung cancer, respectively. Conclusions: Understanding the diversity of genetic markers in Amazonian Amerindian is crucial to the implementation of pharmacogenomic-guided oncology treatment protocols, since pharmacogenomic data validated in other ancestral groups may not be fully applicable in these populations due to their unique genetic profile. Keywords: Exome, Native American populations, fluoropyrimidine, platinum-based drugs, tamoxifen, gefitinib.