Frecuencia de los polimorfismos CYP1A1*2A y deleción del gen GSTM1 en pacientes con carcinoma de células escamosas de laringe en relación al hábito tabáquico: estudio piloto en Chile / Frequency of CYP1A1*2A and GSTM1 gene polymorphisms in Chilean patients with squamous cell carcinoma of the larynx in relation to smoking habit: a pilot study

Introducción: Entre los factores de riesgo para cáncer laríngeo (CL) son relevantes el consumo de tabaco y alcohol. Estos xenobióticos son metabolizados por un grupo de enzimas, entre las cuales están CYP1A1 y GSTM1, cuyas variantes polimórficas se postulan como factores de riesgo para esta enfermedad. Objetivos: Describir la frecuencia de las variantes de los polimorfismos de CYP1A1 y GSTM1 en un grupo de pacientes diagnosticados con CL. Analizar la posible correlación entre las variantes genéticas de ambas enzimas y la presencia de CL. Evaluar la influencia del hábito tabáquico en el riesgo de aparición de cáncer escamoso de laringe en pacientes con genotipos de riesgo. Material y método: Se seleccionaron 35 pacientes con CL entre los años 2000 y 2010 en Servicio de Otorrinolaringología del HBLT y 124 controles reclutados en el Centro de Investigaciones Farmacológicas y Toxicológicas (IFT). A todos los individuos se les registraron datos demográficos y extrajo una muestra de sangre para analizar las variantes polimórficas de CYP1A1 y GSTM1, mediante PCR-RFLP. Resultados: De un total de 35pacientes 54,3% presentan el genotipo GSTM1 (-/-) y 17,1% el genotipo CYP1A1*2A C/C. En el grupo control (n =140) estas frecuencias fueron de 19,35°% y 10,48%o, respectivamente. Se observó una correlación entre GSTM1 y el CL, estratificado por el hábito tabáquico y alcohólico. No se encontraron relaciones estadísticamente significativas con el hábito alcohólico y/o tabáquico. No se observaron asociaciones entre la patología y la combinación de genotipos o entre genotipos y el hábito tabáquico o alcohólico. Conclusiones: Los resultados muestran una asociación estadísticamente significativa entre la deleción de GSTM1 (-/-) y el riesgo de presentar CL, lo que refleja el importante papel que juega esta enzima en la desintoxicación de compuestos cancerígenos. Sin embargo, se requiere incrementar el número de pacientes para establecer apropiadamente la relación genético-ambiental que permite adjudicar un papel relevante a estos biomarcadores.

Introduction: Tobacco and alcohol consumption are recognized risk factors for squamous cell carcinoma of the larynx. These xenobiotics are metabolized by numerous enzymes, among which, CYP1A1 and GSTM1 gene polymorphisms have been identified as risk factors for developing tobacco related cancers as lung and laryngeal carcinomas. Nevertheless, these polymorphisms have not been studied in Chilean patients with squamous cell carcinoma of the larynx. Aim: To describe, for the first time, the frequency of CYP1A1 and GSTM1 gene polymorphisms in Chilean patients with squamous cell carcinoma of the larynx. Material and method: We conducted a case-control study. The case group consisted of 35 Chilean patients with squamous cell carcinoma of the larynx; the control group was formed by 124 Chilean subjects without cancer diagnosis. Demographic data as age, sex and quantification of tobacco smoking and alcohol consumption were recorded in all individuals. CYP1A1 and GSTM1 gene polymorphisms were evaluated by polymerase chain reaction and restriction enzymes (PCR-RFLP). Results: The frequency of CYP1A1*2A C/C genotype was 54, 3°% among laryngeal cancerpatients and 17,1%% among control subjects. The frequency ofGSTM1 (-/-) genotype was 19,35 %% among laryngeal cancer patients and 10,48%% among control subjects. There were no statistically significant relationships between this gene polymorphisms and tobacco smoking or alcohol consumption. There were no associations between the presence of both gene polymorphisms in the same individual and the presence of laryngeal cancer. Interestingly we found an OR of 8.69 (CI 2.90 to 26.01) for GSTM1 (-/-) polymorphism and laryngeal cancer, stratified by tobacco smoking and alcohol consumption. Conclusions: Our work shows that the deletion of GSTM1 could be an important risk factor for squamous cell carcinoma of the larynx in Chilean patients. This finding reflects the important role that detoxification of carcinogenic compounds plays in Chilean population. However, it is necessary to increase the number of studied patients to properly establish the genetic-environmental relationship ascribed to these biomarkers.

Variantes alélicas de CYP1A1 y GSTM1 como biomarcadores de susceptibilidad a cáncer gástrico: influencia de los hábitos tabáquico y alcohólico / Cytochrome P4501A1 (CYP1A1), glutathione S transferase M1 (GSTM1) polymorphisms and their association with smoking and alcohol consumption as gastric cancer susceptibility biomarkers

Background: Gastric cancer (GaC) is the second cause of death by cancer in the world and one of the first causes in Chile. However, the burden of this disease shows remarkable worldwide variation probably explained by environmental and genetic factors. The role of susceptibility low penetrance genes and environmental and dietary factors in the etiology of gastric cancer is not well-known. Aim: To analyze the possible association between CaG susceptibility, genetic (CYP1A1 and GSTM1 polymorphisms) and environmental (tobacco and alcohol) factors. Patients and Methods: In a case-control study, we included 73 patients with a pathologically diagnosed GaC and 263 controls. DNA was extracted from peripheral blood to detect allele variants for CYP1A1 and GSTM1, using polymerase chain reactions and digestion with restriction enzymes. Results: There was a clear association of smoking and alcohol ingestion with GaC with odds ratios (OR) of 2.54 (95 percent confidence intervals (CI) of 1.45-4.46 and OR of 3.36 (95 percent CI 1.76-6.41), respectively. Polymorphic variants of CYP1A1 and GSTM1 had no association with GaC. However, the m2 variant of CYP1A1 significantly modifies the risk induced by tobacco or alcohol (OR 13.65; 95 percent CI 3.15-59.05 y 8.37; 95 percent CI 1.86-37.64, respectively). Conclusions: Subjects that carry the m2 allelic variant of CYP1A1 and are exposed to tobacco smoke or alcohol have a significantly higher risk of developing gastric cancer.

Interacciones genéticas y genético-ambientales como efecto modificador del riesgo de cáncer de próstata: un diseño case-only / Gene-gene and gene-environment interactions as modifier factors of prostatic cancer risk: a case-only design study

Background: The role of susceptibility low penetrance genes and environmental factors in the etiology of prostate cancer (PCa) is unclear, but may involve in some cases multiple alleles at multiple loci. Aim: To evaluate the association of gene-gene and gene-environment interactions with PCa. Patients and methods: One hundred three subjects with biopsy proven PCa were studied, using a case-only design. All were interrogated about smoking habits. Polymorphisms for Glutathione-S-transferase (GST) and Cytochrome P4501A1 (CYP1A1), were measured in DNA extracted from peripheral Iymphocytes, using a restriction fragment length polymorphism analysis. Results: Our findings suggest that gene-gene interactions between GSTT1 and CYP1A1 high risk genotypes were positive modifiers and had a high predictive value for the presence of PCa, compared with non-susceptibility genotypes. The interaction between susceptibility genotypes and smoking did not modify the risk for PCa. Conclusions: Gene-gene interactions may play a role modulating the susceptibility to PCa in a proportion of affected individuals (Rev Méd Chile 2004; 132: 961-66).