Factores genéticos relacionados con la variabilidad en la respuesta a la quimioterapia en pacientes con cáncer testicular

El cáncer testicular (CT) es un tumor maligno que en Chile presenta tasas de incidencia y mortalidad superiores a las tasas mundiales. La familia de genes de Citocromo P450 y Glutatión-S-Transferasas (GSTs) participan en la biotransformación y desintoxicación de fármacos y xenobióticos. Mutaciones en estos genes, y en enzimas de reparación del ADN, han sido asociadas a una mayor incidencia de diversos tipos de cáncer y a un mayor riesgo de presentar reacciones adversas a medicamentos (RAM). Los objetivos de esta tesis fueron: relacionar la presencia de polimorfismos genéticos en CYP1A1, CYP3A4, GST y ERCC, así como factores no genéticos, sobre el riesgo de desarrollar cáncer testicular y el análisis del impacto de los polimorfismos de CYP3A4, GST y BLMH en el riesgo de presentar RAM en pacientes con cáncer testicular. Metodología: Se reclutaron 539 voluntarios de población chilena (PCh) y 234 pacientes con CT. El análisis genotípico fue realizado mediante qPCR y PCR-RFLP. Resultados: Las variantes genéticas de CYP1A1*2C (OR=3,00), GSTT1 (OR=2,08) y GSTP1 (A/G OR=2,86 y G/G OR=4,00) aumentan el riesgo de desarrollar CT, además de los antecedentes familiares de cáncer (OR=2,53) o el hábito tabáquico (OR=2,04). Los resultados del análisis multivariable muestran que la presencia de polimorfismos en GSTP1 (A/G y G/G) en conjunto con el hábito tabáquico y los antecedentes familiares de cáncer explican un 12 % del riesgo de desarrollar cáncer testicular en población chilena. Conclusión:, Los resultados de este estudio han permitido identificar factores genéticos y no genéticos que se asocian a la aparición de cáncer testicular CT, y permiten disponer de una herramienta de predicción parcial del riesgo. No se observaron asociaciones significativas entre variantes genéticas y RAM.Testicular cancer (TC) is a malignant tumor that in Chile has incidence and mortality rates higher than the world rates. The family of genes of Cytochrome P450 and Glutathione-S-transferases (GSTs) participate in the biotransformation and detoxification of xenobiotics. Mutations in these genes and in DNA repair enzymes have been associated with a higher incidence of various types of cancer, and an increased risk of presenting adverse reactions to drugs (ADR). The objectives of this Thesis were: to relate the presence of genetic polymorphisms in CYP1A1, CYP3A4, GST and ERCC and non-genetic factors on the risk of developing testicular cancer. In addition, the analysis of the impact of CYP3A4, GST, and BLMH polymorphisms with the risk of presenting ADR in patients suffering from TC. Methods: We recruited 539 volunteers from the Chilean population (PCh) and 234 patients with TC. The genotypic analysis was performed by using qPCR and PCR-RFLP. Results: Variant alleles that increase the risk of developing TC are CYP1A1*2C (OR = 3.00), GSTT1(-) (OR = 2.08) and GSTP1 (A/G OR = 2.86; G/G OR = 4.00), besides family history of cancer (OR = 2.53) or smoking (OR = 2.04). The results of the multivariate analysis show that the presence of variant alleles in GSTP1 (A/G and G/G) together with smoking habit and family history of cancer explain 12% of the risk of developing testicular cancer in the Chilean population. Conclusions: In this study, we identified genetic and non-genetic factors associated to CT, which make constitute a tool for partial risk prediction. We did not identify significant associations between genetic variants and ADR

Influencia de polimorfismos genéticos de CYP3A4/5 en la farmacocinética de levonorgestrel: estudio piloto

Introduction. Levonorgestrel a synthetic progestagen used for endometriosis, dysmenorrhea and emergency contraception, is quickly and completely absorbed in the digestive tract. levonorgestrel is predominantly metabolised through hepatic routes that utilise the CYP3A system (CYP3A4 and CYP3A5). Objective. This study aimed to evaluate the association between variant alleles of CYP3A4*1B and CYP3A5*3 polymorphisms and the pharmacokinetics of levonorgestrel. Materials and methods. A group of 17 adult female healthy volunteers who signed an informed consent were genotyped for CYP3A4 and CYP3A5 through PCR-RFLP. Volunteers were submitted to pharmacokinetic analysis where, after a 12-hour overnight fast, they received a single oral dose of 0.75 mg of levonorgestrel. Serial blood samples were obtained (0 to 24 hours), and levonorgestrel concentrations were determined by UPLC-MS/MS to determine pharmacokinetic parameters. The procedures employed herein were performed according to the Declaration of Helsinki and Good Clinical Practices standards. Results. Observed genotype frequencies in the studied group for CYP3A4*1B were 11.8% for *1B/*1B, 5.8% for *1/*1B and 82.4% for *1/*1. CYP3A5*3 frequencies were 70.5% for *3/*3, 23.5% for *1/*3 and 6.5% for *1/*1. A high pharmacokinetic variability between volunteers was observed, but no statistical association of pharmacokinetic parameters was found within the studied CYP3A4/5 polymorphisms. Conclusions. Genetic polymorphisms could be important factors in determining inter-patient variability in plasma levonorgestrel concentrations, which in this study were not significantly associated with the presence of CYP3A4*1B and CYP3A5*3 polymorphisms. Therefore, due to the significant inter-patient variability that we observed during the course of this study, it is necessary to carry out studies with larger number of volunteer