HUJBB, Belem, Brazil
Marianne R. Fernandes , Danielle Feio da Costa , Williams Fernandes Barra , Juliana Carla Gomes Rodrigues , Millene Arruda Bechara Gonçalves , Raiza Martins Fontoura , Francisco Cezar Aquino de Moraes , Esdras Edgar Batista Pereira , Rommel Mario Rodriguez Burbano , Paulo Pimentel Assumpção , Ana Latorre-Pellice , Olalla Maroñas Amigo , Raquel Cruz Guerrero , Sidney Emanuel Batista dos Santos , Ángel María Carracedo Álvarez , Ney Pereira Carneiro dos Santos
Background: Fluoropyrimidine-based treatments are still considered challenging due to the wide variability in efficacy and toxicity rates presented by patients. This variability can be explained, partially, by individual genetic differences that contribute significantly to the response of the drug, with 30% of patients experiencing severe toxicity related to dihydropyrimidine dehydrogenase (DPD) deficiency and 5-Fluorouracil (5-FU) metabolism. Methods: This study analyzed the exome of the main genes involved in the fluoropyrimidine metabolism pathway (DPYD, TYMS / ENOSF1, MTHFR, CDA, CES2, and UGT1A1) in seven patient who developed fatal 5-FU toxicity diagnosed with gastric or colorectal adenocarcinoma and underwent fluoropyrimidine-based cancer treatment. The genotyping service was carried out at CEGEN-PRB3-ISCIII; it is supported by grant PT17/0019, of the PE I+D+i 2013-2016, funded by ISCIII and ERDF. Results: A total of 74 genetic polymorphisms were identified, 25 of which stand out due to their potential role in the safety of 5-FU administration. Eight variants are exclusive of the studied population (two found in the DPYD gene, two in the MHFR, one in the CES2, and three in the UGT1A1 gene) and 17 have already been associated with fluoropyrimidine efficacy and/or toxicity events: 10 of them are located in the DPYD gene (rs1801159, rs2297595, rs72728438, rs17376848, rs1801160, rs1801265, rs22447512, rs5568, rs56038477, rs56276561, and rs56293913), two in the intergenic region of the TYMS/ENOSF1 genes (rs11280056 and rs699517), two in the MTHFR gene (rs1801131 and rs1801133) and three in the CDA gene (rs1048977, rs2072671, and rs3215400). Conclusions: The current study has allowed us to obtain a global profile of genetic variants in the pharmacokinetic and pharmacodynamic pathways of fluoropyrimidines in patients with high genetic miscegenation in the northern region of Brazil who have evolved to death due to the fatal toxicity resulting from 5-FU-based therapies. Keywords: Pharmacogenomics; Exome; 5-Fluorouracil; Drug toxicity; Brazil.
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