Influence of FPGS, ABCC4, SLC29A1, and MTHFR genes on the pharmacogenomics of fluoropyrimidines in patients with gastrointestinal cancer from the Brazilian Amazon

Cancer Chemother Pharmacol. 2021 Nov;88(5):837-844. doi: 10.1007/s00280-021-04327-w. Epub 2021 Jul 31.

Abstract

Purpose: Fluoropyrimidines are one of the most used drug class to treat cancer patients, although they show high levels of associated toxicity. This study analyzed 33 polymorphisms in 17 pharmacogenes involved with the pharmacogenomics of fluoropyrimidines, in gastrointestinal cancer patients undergoing fluoropyrimidine-based treatment in the Brazilian Amazon.

Methods: The study population was composed of 216 patients, 92 of whom have an anatomopathological diagnosis of gastric cancer and 124 of colorectal cancer. The single nucleotide polymorphisms (SNP) were genotyped by allelic discrimination using the TaqMan OpenArray Genotyping technology, with a panel of 32 customized assays, run in a QuantStudio ™ 12K Flex Real-Time PCR System (Applied Biosystems, Life Technologies, Carlsbad USA). Ancestry analysis was performed using 61 autosomal ancestry informative markers (AIMs).

Results: The study population show mean values of 48.1% European, 31.1% Amerindian, and 20.8% African ancestries. A significant risk association for general and severe toxicity was found in the rs4451422 of FPGS (p = 0.001; OR 3.40; CI 95% 1.65-7.00 and p = 0.006; OR 4.63; CI 95% 1.56-13.72, respectively) and the rs9524885 of ABCC4 (p = 0.023; OR 2.74; CI 95% 1.14-6.65 and p = 0.024; OR 5.36; IC 95% 1.24-23.11, respectively) genes. The rs760370 in the SLC29A1 gene (p = 0.009; OR 6.71; CI 95% 1.16-8.21) and the rs1801133 in the MTHFR toxicity (p = 0.023; OR 3.09; CI 95% 1.16-8.21) gene also demonstrated to be significant, although only for severe toxicity. The results found in this study did not have statistics analysis correction.

Conclusion: Four polymorphisms of the ABCC4, FPGS, SLC29A1, and MTHFR genes are likely to be potential predictive biomarkers for precision medicine in fluoropyrimidine-based treatments in the population of the Brazilian Amazon, which is constituted by a unique genetic background.

Keywords: ABCC4; FPGS; Fluoropyrimidine; MTHFR; Pharmacogenomics; SLC29A1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Combined Chemotherapy Protocols / adverse effects
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Brazil
  • Camptothecin / analogs & derivatives
  • Camptothecin / pharmacology
  • Equilibrative Nucleoside Transporter 1 / genetics
  • Female
  • Fluorouracil / administration & dosage
  • Fluorouracil / pharmacokinetics
  • Fluorouracil / pharmacology
  • Gastrointestinal Neoplasms / drug therapy*
  • Gastrointestinal Neoplasms / genetics*
  • Humans
  • Leucovorin / pharmacology
  • Male
  • Methylenetetrahydrofolate Reductase (NADPH2) / genetics
  • Middle Aged
  • Multidrug Resistance-Associated Proteins / genetics
  • Organoplatinum Compounds / pharmacology
  • Peptide Synthases / genetics
  • Pharmacogenomic Variants
  • Polymorphism, Single Nucleotide

Substances

  • ABCC4 protein, human
  • Equilibrative Nucleoside Transporter 1
  • Multidrug Resistance-Associated Proteins
  • Organoplatinum Compounds
  • SLC29A1 protein, human
  • MTHFR protein, human
  • Methylenetetrahydrofolate Reductase (NADPH2)
  • Peptide Synthases
  • folylpolyglutamate synthetase
  • Leucovorin
  • Fluorouracil
  • Camptothecin

Supplementary concepts

  • Folfox protocol
  • IFL protocol