Dynamic Effects of CYP2D6 Genetic Variants in a Set of Poor Metaboliser Patients with Infiltrating Ductal Cancer Under Treatment with Tamoxifen

Yeimy Viviana Ariza Márquez,Juvenal Yosa Reyes,Ignacio Briceño,Fabio Aristizábal,Luis Fernando Niño

doi:10.1038/s41598-018-38340-6

Abstract

Breast cancer is a group of multigenic diseases. It is the most common cancer diagnosed among women worldwide and is often treated with tamoxifen. Tamoxifen is catalysed by cytochrome P450 2D6 (CYP2D6), and inter-individual variations in the enzyme due to single nucleotide polymorphisms (SNPs) could alter enzyme activity. We evaluated SNPs in patients from Colombia in South America who were receiving tamoxifen treatment for breast cancer. Allelic diversity in the CYP2D6 gene was found in the studied population, with two patients displaying the poor-metaboliser phenotype. Molecular dynamics and trajectory analyses were performed for CYP2D6 from these two patients, comparing it with the common allelic form (CYP2D6*1). Although we found no significant structural change in the protein, its dynamics differ significantly from those of CYP2D6*1, the effect of such differential dynamics resulting in an inefficient enzyme with serious implications for tamoxifen-treated patients, increasing the risk of disease relapse and ineffective treatment.

Highlights

Www.nature.com/scientificreports tumors) after 5 years of treatment with tamoxifen, for invasive ER+ tumours in premenopausal women[14,15]
Over 140 allelic variants of cytochrome P450 2D6 (CYP2D6) have been described, and several of them are associated with reduced or no activity. These complex pharmacogenetic relationships have been established by the efficiency of tamoxifen transformation, which can be correlated with CYP2D6 genes and single nucleotide polymorphisms (SNPs) association[17,18,19,20,21]
A comparison of the three metabolising states [0, poor metaboliser (PM) (Poor); 1, intermediate metaboliser (IM) (Intermediate); and 2, extensive metaboliser (EM) (Extensive)] showed that endoxifen concentration increased in the EM and IM patients, indicating that tamoxifen had been metabolised

Summary

Introduction

Www.nature.com/scientificreports tumors) after 5 years of treatment with tamoxifen, for invasive ER+ tumours in premenopausal women[14,15]. Studies involving 123 participants from the academic and student staff at Pontificia Universidad Javeriana (Bogota) and 148 participants of the Colombian Air Force school identified the CYP2D6 *2, *3, *4, *5, *6, *10, *35 and *41 alleles[31,32]. Despite these studies, there is a lack of information about CYPD26 variants in Colombian population with BC and the effectiveness of tamoxifen. The goal was to identify the genotypes and intermediary metabolites of tamoxifen in this Colombian population and to define the influence of CYP2D6 mutations on the enzyme’s structure and dynamics

Methods

Results

Conclusion