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4. Influence of the glutathione s-transferase gene polymorphisms on the susceptibility to basal cell skin carcinoma

Author

Leite, Janaína L, Morari, Elaine C, Granja, Fabiana, Campos, Gabriela M, Guilhen, Ana CT, and Ward, Laura S

Subjects
Glutathione S-transferase, Carcinoma, basal cell, Polymorphism, genetic
Abstract

Background: The identification of groups at high risk is fundamental to determine preventive strategies for skin cancer. Destructive reactive oxygen species produced by UVA or chemical carcinogens are metabolized by a series of enzymes. Polymorphisms of genes encoding for these enzymes may produce defective proteins with a diminished ability to detoxify a wide range of carcinogens. Aims: To ascertain the influence and potential interactions of several polymorphisms of genes encoding four important antioxidant GST enzymes in the susceptibility to cancer among Brazilians. Material and methods: We compared the genotypes of Glutathione S-Transferase mu, theta, pi and omega (GSTM1, GSTT1, GSTP1 and GSTO2) in a group of 102 patients with skin lesions and 124 controls. Results: Patients with Basal Cell Skin Carcinoma (BCC) presented the combined GSTM1-GSTT1+ genotype more frequently (49.1%) than controls (29.8%) (Fisher test; p =0.04), conferring a 2.273 (Odds Ratio; 95% CI =1.199-4.308) higher risk for BCC. We were not able to find any other association between genotypes or between any genotype and the patients' clinical features. Conclusions: The GST profile may help identify Brazilian individuals at higher risk for BCC Antecedentes: La identificación de grupos en riesgo elevado es fundamental en la determinación de las estrategias preventivas para el cáncer de la piel, el maligno humano más común. Las especies reactivas destructivas del oxígeno producidas por UVA o los agentes carcinógenos químicos son metabolizadas por una serie de enzimas. Los polimorfismos de los genes que codifican para estas enzimas pueden producir las enzimas defectuosas con una capacidad disminuida de desintoxicar una amplia gama de agentes carcinógenos. Objetivo: Este estudio fue diseñado para comprobar las interacciones de la influencia y del potencial de varios polimorfismos de los genes que codificaban 4 enzimas importantes del antioxidante GST en la susceptibilidad al cáncer entre brasileños. Métodos: Comparamos los genotipos del mu del S-Transferase del Glutathione, de la theta, de pi y de Omega (GSTM1, GSTT1, GSTP1 y GSTO2) en un grupo de 102 lesiones de piel y de 124 controles. Resultados: Los pacientes con el carcinoma basocelular (BCC) presentaron el genotipo combinado de GSTM1-GSTT1+ más frecuente (49,1%) que los controles (29,8%) (Fisher test; p =0,04), confiriendo 2.273 (Odds Ratio 95% CI =1.199-4.308) un riesgo más alto para BCC. No encontramos ninguna otra asociación entre los genotipos o entre ningún genotipo y características clínicas de los pacientes. Conclusiones: Sugerimos que el perfil de GST pueda ayudar a identificar a individuos brasileños en un riesgo más alto para BCC

Published
2007

11. Smoking and susceptibility to thyroid cancer: an inverse association with CYP1A1allelic variants

Author

Bufalo, Natassia E, Leite, Janaina L, Guilhen, Ana C T, Morari, Elaine C, Granja, Fabiana, Assumpcao, Ligia V M, and Ward, Laura S

Abstract

In contrast to most human malignancies, epidemiologic studies have frequently reported a reduced risk of differentiated thyroid cancer in tobacco consumers. Cytochrome P4501A1 (CYP1A1) gene variants may be related to an increased capacity to activate polycyclic aromatic hydrocarbons, producing highly reactive electrophilic intermediates that might damage DNA. Hence, the germline inheritance of a wild-type CYP1A1gene may decrease the susceptibility for thyroid cancer. The present study was designed to investigate CYP1A1(m1and m2) role in thyroid tumorigenesis and its connection with GSTM1, GSTT1, GSTP1, GSTO1,and codon 72of p53genotypes. A total of 248 patients with thyroid nodules, including 67 benign goiters, 13 follicular adenomas, 136 papillary carcinomas, and 32 follicular carcinomas, and 277 controls with similar ethnic backgrounds were interviewed on their lifetime dietary and occupational histories, smoking habit, previous diseases, and other anamnestic data. DNA was extracted from a blood sample and submitted to PCR-restriction fragment length polymorphism assays. The wild-type CYP1A1m1genotype was more frequent among papillary carcinoma patients (74.26%) than in the control population (62.45%; P= 0.0147), reducing the risk for this type of cancer (odds ratio = 0.564; 95% confidence interval = 0.357–0.894). A multiple logistic regression analysis showed an inverse correlation between cigarette smoking (P= 0.0385) and CYP1A1germline inheritance (P= 0.0237) with the susceptibility to papillary carcinomas. We were not able to find any correlation between smoking, clinical features, parameters of aggressiveness at diagnosis or during follow-up, and any of the GSTor CYPgenotypes considered separately or in different combinations. We suggest that CYP1A1genotype might be associated with the reported reduced risk to papillary carcinomas among smokers.

Published
2006
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12. Role of the N-acetyltransferase 2 detoxification system in thyroid cancer susceptibility.

Author

Guilhen AC, Bufalo NE, Morari EC, Leite JL, Assumpcao LV, Tincani AJ, and Ward LS

Subjects
Brazil, Case-Control Studies, Female, Genetic Predisposition to Disease, Haplotypes, Humans, Inactivation, Metabolic, Male, Middle Aged, Phenotype, Polymyalgia Rheumatica, Prospective Studies, Risk Factors, Arylamine N-Acetyltransferase genetics, Thyroid Neoplasms genetics
Abstract

Purpose: Genetic polymorphisms in genes encoding for enzymes involved in the biotransformation of carcinogens have been shown to be relevant as risk for cancer and may be of considerable importance from a public health point of view. Considering that N-acetyltransferase 2 (NAT2) polymorphisms modulate the response to ionizing radiation, the strongest risk factor recognized to cause differentiated thyroid cancer (DTC) thus far, we sought to determine the influence of NAT2 detoxification system on thyroid cancer susceptibility., Experimental Design: We conducted a prospective case-control study, comparing 195 patients presenting with DTC that were previously genotyped for GSTT1, GSTM1, GSTP1, and CYP1A1, comprising 164 papillary carcinomas and 31 follicular carcinomas, with 196 control individuals paired for gender, age, ethnicity, diet routine, lifetime occupational history, smoking history, general health conditions, and previous diseases. We used PCR-RFLP assays and the combination of 6 variant alleles to define 18 NAT2 haplotypes that characterized slow, intermediate, or rapid phenotypes., Results: A multivariate logistic regression analysis identified the presence of *12A and the absence of *12B, *13, *14B, *14D, *6A, and *7A NAT2 haplotypes as risk factors for DTC. The inheritance of a rapid acetylation phenotype doubled the risk for a papillary carcinoma (odds ratio, 2.024; 95% confidence interval, 1.252-3.272). We found no relationship between genotypes and clinical, pathologic, or laboratory features of patients or between genotypes and outcome., Conclusions: We showed that NAT2 genotypes and the NAT2 rapid acetylation phenotype are important susceptibility factors for DTC, suggesting that NAT2 detoxification system is involved in this tumor pathogenesis.

Published
2009
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