Relación entre polimorfismos genéticos de Glutatión-S-Transferasas y Glicoproteína P en combinación con antecedentes familiares de cáncer, hábitos tabáquicos y/o alcohólicos, con el riesgo de desarrollar cáncer testicular y con la aparición de reacciones adversas a quimioterapia basada en cisplatino
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2017
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es
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Universidad Andrés Bello
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Resumen
Introducción: El cáncer testicular (CaT) en Chile presenta más altas tasas de incidencia y
mortalidad que en el mundo. La familia de genes glutatión-S-transferasas (GSTs) que
codifican para enzimas de metabolización de fase II, tienen función en la biotransformación
y desintoxicación de xenobióticos, incluyendo agentes carcinógenos, mutágenos y
medicamentos antineoplásicos. La glicoproteína P es codificada por un gen de resistencia a
multidroga (MDR1) y es un transportador de cassette unido a ATP (ABC) que es clave en la
absorción y el eflujo de fármacos. Mutaciones en estos genes han sido asociadas a mayor
incidencia de diversos tipos de cánceres. El objetivo de este trabajo fue relacionar la presencia
de los polimorfismos GSTP1 (rs1695), MDR1 (rs1045642), GSTT1 (-) y GSTM1 (-) y los
factores modificadores del riesgo, individualmente o en combinación con el riesgo de
desarrollar CaT y la aparición de reacciones adversas (RAMs) en pacientes con CaT.
Metodología: Se obtuvo ADN genómico de 247 voluntarios de población chilena (PCh) y
200 pacientes con CaT, bajo protocolo autorizado por comité de ética. Los análisis
genotípicos fueron realizados mediante Real Time-PCR y PCR-RFLP.
Resultados: El polimorfismo GSTP1 presenta una frecuencia alélica (FA) del alelo G de 0,36
en PCh y 0,49 en pacientes con CaT y se asocia con el riesgo en desarrollar CaT (OR =
2,09; IC = 1,27-3,43; p-value 0,004) para el genotipo A/G y G/G (OR = 5,24; IC = 2,35-11,7;
p-value <0,001). Para GSTT1 (-) la frecuencia genotípica (FG) es de 7% en PCh y de 13%
en CaT. GSTM1(-) presenta una FG de 34% en PCh y 37% en pacientes con CaT, MDR1
presenta en PCh una FA de T de 0,36 y 0,41 en pacientes con CaT y muestra asociación con
el desarrollo de CT (OR = 3,80; IC = 1,43-10,08; p-value 0,007). Para GSTP1, se obtuvo
asociación significativamente aumentada con antecedentes de cáncer, hábito tabáquico y
alcohólico para el genotipo G/G. MDR1 se vio asociada con los factores modificadores sólo
para el genotipo T/T. No se vieron asociaciones con RAMs. Conclusiones: La presencia de
los polimorfismos en GSTP1 y MDR1, en combinación con el hábito tabáquico y
antecedentes de cáncer explican un 24% del riesgo de desarrollar cáncer testicular en
población chilena. No se encontró asociación entre los genotipos estudiados y la presencia
de RAM hematológica o gástrica.
Introduction: Testicular cancer (TC) in Chile has the highest incidence and mortality all over the world. The family of glutathione-S-transferases (GSTs) genes encoding for phase II metabolism enzymes, has a role in the biotransformation and detoxification of xenobiotics, including carcinogens, mutagens and antineoplastic drugs. P glycoprotein is encoded by a multidrug resistance gene (MDR1) and is a cassette transporter bound to ATP (ABC) that is key in drug absorption and efflux. Mutations in these genes have been associated with a higher incidence of various types of cancers. The objective of this work was to relate the presence of the GSTP1 (rs1695), MDR1 (rs1045642), GSTT1 (-) and GSTM1 (-) polymorphisms and the risk modifying factors: family history of cancer, smoking and alcoholic habit, individually or in combination with the risk of developing TC and the appearance of adverse reactions to drugs (ADRs) to cisplatin-based chemotherapy in patients with TC.. Methodology: Genomic DNA was obtained from 247 volunteers of the Chilean population (CP) and 200 patients with TC, under protocol approved by ethic commitee. Genotypic analyses were performed by Real Time-PCR and PCR-RFLP. Results: The GSTP1 polymorphism has an allelic frequency (AF) of the G allele of 0.36 in PCh and 0.49 in patients with TC, associated with an increased risk in TC (OR = 2.09; CI = 1,27-3,43; pvalue 0,004) for genotype A/G and G/G (OR = 5.24; CI = 2,35-11,7; p-value <0,001). For GSTT1 (-) the genotypic frequency (GF) is 7% in CP and 13% in TC. GSTM1 (-) presents a GF of 34% in CP and 37% in patients with TC. MDR1 for CP, an AF of A of 0.36 and 0.41 in patients with TC, and is associated with the risk in developing (OR = 3.80; CI = 1.43- 10.08; p-value 0,007). For GSTP1, it has been registered with an increase in cancer capacity, smoking and alcohol habit for the G/G genotype. MDR1 was associated with the modifying factors only for the T/T genotype. No associations with ADRs were seen. Conclusions: The presence of studied GSTP1 and MDR1 polymorphisms, combined with smoking habit and family history of cancer explain 24% of the risk of developing testicular cancer in the Chilean population. No association was found between the genotypes studied and the presence of hematologic or gastric ADRs.
Introduction: Testicular cancer (TC) in Chile has the highest incidence and mortality all over the world. The family of glutathione-S-transferases (GSTs) genes encoding for phase II metabolism enzymes, has a role in the biotransformation and detoxification of xenobiotics, including carcinogens, mutagens and antineoplastic drugs. P glycoprotein is encoded by a multidrug resistance gene (MDR1) and is a cassette transporter bound to ATP (ABC) that is key in drug absorption and efflux. Mutations in these genes have been associated with a higher incidence of various types of cancers. The objective of this work was to relate the presence of the GSTP1 (rs1695), MDR1 (rs1045642), GSTT1 (-) and GSTM1 (-) polymorphisms and the risk modifying factors: family history of cancer, smoking and alcoholic habit, individually or in combination with the risk of developing TC and the appearance of adverse reactions to drugs (ADRs) to cisplatin-based chemotherapy in patients with TC.. Methodology: Genomic DNA was obtained from 247 volunteers of the Chilean population (CP) and 200 patients with TC, under protocol approved by ethic commitee. Genotypic analyses were performed by Real Time-PCR and PCR-RFLP. Results: The GSTP1 polymorphism has an allelic frequency (AF) of the G allele of 0.36 in PCh and 0.49 in patients with TC, associated with an increased risk in TC (OR = 2.09; CI = 1,27-3,43; pvalue 0,004) for genotype A/G and G/G (OR = 5.24; CI = 2,35-11,7; p-value <0,001). For GSTT1 (-) the genotypic frequency (GF) is 7% in CP and 13% in TC. GSTM1 (-) presents a GF of 34% in CP and 37% in patients with TC. MDR1 for CP, an AF of A of 0.36 and 0.41 in patients with TC, and is associated with the risk in developing (OR = 3.80; CI = 1.43- 10.08; p-value 0,007). For GSTP1, it has been registered with an increase in cancer capacity, smoking and alcohol habit for the G/G genotype. MDR1 was associated with the modifying factors only for the T/T genotype. No associations with ADRs were seen. Conclusions: The presence of studied GSTP1 and MDR1 polymorphisms, combined with smoking habit and family history of cancer explain 24% of the risk of developing testicular cancer in the Chilean population. No association was found between the genotypes studied and the presence of hematologic or gastric ADRs.
Notas
Tesis (Bioquímico, Magíster en Bioquímica)
Esta tesis se realizó en el Laboratorio de Carcinogénesis Química y Farmacogenética, Departamento de Oncología Básico Clínica de la Facultad de Medicina de la Universidad de Chile y fue financiada por el proyecto FONDECYT Regular N°1140434.
Esta tesis se realizó en el Laboratorio de Carcinogénesis Química y Farmacogenética, Departamento de Oncología Básico Clínica de la Facultad de Medicina de la Universidad de Chile y fue financiada por el proyecto FONDECYT Regular N°1140434.
Palabras clave
Cáncer Testicular, Quimioterapia, Polimorfismo Genético, Efectos Adversos, Cisplatino, Investigaciones, Chile