RESUMEN

OBJECTIVE: Immune responses against differentiated thyroid carcinomas (DTC) have long been recognized. We aimed to investigate the role of immune cell infiltration in the progression of DTC. DESIGN: We studied 398 patients - 253 with papillary and 13 with follicular thyroid cancers, as well as 132 with nonmalignant tissues. PATIENTS AND MEASUREMENTS: Immune cell infiltration was identified using CD3, CD4, CD8, CD20, CD68 and FoxP3 immunohistochemical markers. In addition, we assessed colocalization of CD4 and IL-17 to identify Th17 lymphocytic infiltration and colocalization of CD33 and CD11b to identify infiltration of myeloid-derived suppressor cells (MDSC). RESULTS: Immune cells infiltrated malignant tissues more often than benign lesions. The presence of chronic lymphocytic thyroiditis (CLT) concurrent to DTC, CD68+, CD4+, CD8+, CD20+, FoxP3+ and Th17 lymphocytes but not MDSCs was associated with clinical and pathological features of lower tumour aggressiveness and a more favourable patient outcome. A log-rank test confirmed an association between concurrent CLT, tumour-associated macrophage infiltration, and CD8+ lymphocytes and an increased in disease-free survival, suggesting that evidence of these immune reactions is associated with a favourable prognosis. CONCLUSION: Our data suggest that the tumour or peri-tumoural microenvironment may act to modify the observed pattern of immune response. Immune cell infiltration and the presence of concurrent CLT helped characterize specific tumour histotypes associated with favourable prognostic features.

Asunto(s)

Linfocitos Infiltrantes de Tumor/patología , Macrófagos/patología , Neoplasias de la Tiroides/inmunología , Neoplasias de la Tiroides/patología , Adenocarcinoma Folicular/inmunología , Adenocarcinoma Folicular/patología , Adulto , Carcinoma/inmunología , Carcinoma/patología , Carcinoma Papilar , Femenino , Humanos , Linfocitos/inmunología , Linfocitos/patología , Linfocitos Infiltrantes de Tumor/inmunología , Macrófagos/inmunología , Masculino , Persona de Mediana Edad , Células Mieloides/inmunología , Células Mieloides/patología , Pronóstico , Cáncer Papilar Tiroideo

RESUMEN

OBJECTIVE: We aimed to investigate the use of NIS mRNA and protein expression as a diagnostic and/or prognostic marker in patients with differentiated thyroid cancer (DTC). DESIGN: This is a case-control study. PATIENTS: We studied 397 thyroid nodules tissue samples, including 224 papillary thyroid carcinomas (PTCs), 41 follicular carcinomas, 58 nodular goiters, 56 follicular adenomas and 18 normal tissues assembled in a tissue microarray. MEASUREMENTS: NIS protein was identified using a monoclonal antibody that labelled only the follicular cell basolateral membrane of all 397 tissue samples. In addition, NIS mRNA was quantified in 145 DTC patients and 85 PTC cases were screened for BRAF(V600E) mutation. RESULTS: We found low NIS mRNA expression and low or negative NIS protein expression in most DTC. NIS expression was lower in DTC patients over 45 years old and in tumours larger than 2 cm. There was a tendency for lower NIS expression in advanced stages and patients presenting recurrences. All 13 DTC patients who succumbed to the disease were NIS negative at immunohistochemistry and had very low mRNA expression. NIS expression was lower in PTC presenting BRAF(V600E) mutation. However, neither NIS immunohistochemical analysis nor NIS mRNA quantified expression could identify individuals with poor prognosis. CONCLUSIONS: Our data suggest that NIS expression may help characterize patients' risk and individuals with a poor response to therapy, but is not useful as a diagnostic or prognostic marker, reinforcing the current concept that an appropriate management of DTC patient is the most important and modifiable prognostic factor.

Asunto(s)

Simportadores/genética , Neoplasias de la Tiroides/patología , Adenocarcinoma Folicular/patología , Adenoma/patología , Adulto , Carcinoma , Carcinoma Papilar , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , ARN Mensajero/análisis , Riesgo , Simportadores/análisis , Cáncer Papilar Tiroideo , Análisis de Matrices Tisulares

RESUMEN

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.

Asunto(s)

Arilamina N-Acetiltransferasa/genética , Neoplasias de la Tiroides/genética , Brasil , Estudios de Casos y Controles , Femenino , Predisposición Genética a la Enfermedad , Haplotipos , Humanos , Inactivación Metabólica , Masculino , Persona de Mediana Edad , Fenotipo , Polimialgia Reumática , Estudios Prospectivos , Factores de Riesgo

RESUMEN

OBJECTIVE: Cigarette smoking is a well-recognized risk factor of Graves' disease and, particularly, Graves' ophthalmopathy. Hence, germline polymorphisms of detoxification genes and genes belonging to the major DNA repair-apoptosis pathways might have an important role in disease susceptibility. In addition, as some of these genes are regulated by thyroid hormones, they may affect the patients' outcomes. We aimed to assess the influence of the GST, CYP and TP53 gene polymorphisms in the risk of Graves' disease and its outcome. DESIGN: Prospective case-control study. PATIENTS: A PCR-based strategy was used for GSTT1, GSTM1, GSTP1, CYP1A1 and TP53 codon 72 genotypes in a group of 400 Graves' disease patients, and to compare them to 574 control individuals with similar environmental exposure features. RESULTS: GSTM1 and GSTT1 genotypes were equally distributed in cases and controls, respectively. However, GSTP1 (P < 0.0001), CYP1A1 (P < 0.0033) and Pro/ProTP53 (P < 0.0035) variants appeared more frequently in Graves' disease patients than in controls. A multivariate analysis indicated that cigarette smoking and inheritance of GSTP1, CYP1A1 and Pro/ProTP53 variants were important risk factors for Graves' disease, but only smoking appeared as an independent risk factor for Graves' ophthalmopathy. There was no association between clinical features, including ophthalmopathy or treatment outcome, and the studied genotypes. CONCLUSION: We concluded that GSTP1, CYP1A1 and TP53, but not GSTT1 and GSTM1 germline polymorphisms, may be associated with smoking-related Graves' disease susceptibility and configure a risk profile for the disease. However, these polymorphisms do not influence the patients' response to treatment.

Asunto(s)

Enfermedad de Graves/genética , Polimorfismo Genético , Fumar/genética , Adulto , Antitiroideos/uso terapéutico , Estudios de Casos y Controles , Citocromo P-450 CYP1A1/genética , Femenino , Genotipo , Glutatión Transferasa/genética , Enfermedad de Graves/tratamiento farmacológico , Enfermedad de Graves/radioterapia , Humanos , Radioisótopos de Yodo/uso terapéutico , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Proteína p53 Supresora de Tumor/genética , Adulto Joven

RESUMEN

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.

Asunto(s)

Carcinoma Basocelular/genética , Predisposición Genética a la Enfermedad/genética , Glutatión Transferasa/genética , Polimorfismo Genético/genética , Neoplasias Cutáneas/genética , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma Basocelular/enzimología , Métodos Epidemiológicos , Femenino , Genotipo , Gutatión-S-Transferasa pi/genética , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Longitud del Fragmento de Restricción , Especies Reactivas de Oxígeno/metabolismo , Neoplasias Cutáneas/enzimología

RESUMEN

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 percent) than controls (29.8 percent) (Fisher test; p =0.04), conferring a 2.273 (Odds Ratio; 95 percent 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.

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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 por ciento) que los controles (29,8 por ciento) (Fisher test; p =0,04), confiriendo 2.273 (Odds Ratio 95 por ciento 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.

Asunto(s)

Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Carcinoma Basocelular/genética , Predisposición Genética a la Enfermedad/genética , Glutatión Transferasa/genética , Polimorfismo Genético/genética , Neoplasias Cutáneas/genética , Carcinoma Basocelular/enzimología , Métodos Epidemiológicos , Genotipo , Gutatión-S-Transferasa pi/genética , Polimorfismo de Longitud del Fragmento de Restricción , Especies Reactivas de Oxígeno/metabolismo , Neoplasias Cutáneas/enzimología

RESUMEN

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 CYP1A1 gene may decrease the susceptibility for thyroid cancer. The present study was designed to investigate CYP1A1 (m1 and m2) role in thyroid tumorigenesis and its connection with GSTM1, GSTT1, GSTP1, GSTO1, and codon 72 of p53 genotypes. 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 CYP1A1m1 genotype 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 CYP1A1 germline 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 GST or CYP genotypes considered separately or in different combinations. We suggest that CYP1A1 genotype might be associated with the reported reduced risk to papillary carcinomas among smokers.

Asunto(s)

Citocromo P-450 CYP1A1/genética , Predisposición Genética a la Enfermedad , Fumar , Neoplasias de la Tiroides/genética , Adulto , Anciano , Anciano de 80 o más Años , Alelos , Estudios de Casos y Controles , Femenino , Variación Genética , Genotipo , Gutatión-S-Transferasa pi/genética , Glutatión Transferasa/genética , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Factores de Riesgo , Neoplasias de la Tiroides/enzimología , Proteína p53 Supresora de Tumor/genética

RESUMEN

A common germline polymorphism of p53 gene produces an Arginine to Proline change at aminoacid position 72. The resulting codon 72 variants have been reported associated with tumor susceptibility since they reduce p53 ability to activate apoptosis. Codon 72 polymorphism may play a role in subside vulnerability to different carcinogens and might account for ethnic variations in cancer frequency. Using an allele-specific polymerase chain reaction (PCR), we tested peripheral blood samples from 98 patients with thyroid cancer, including 21 follicular (FC) and 77 papillary carcinomas (PC), 44 patients with benign nodules, including 14 follicular adenomas and 30 goiters and 153 healthy individuals from the same geographical region. Data on lifetime occupational history, smoking history, general health conditions, previous diseases and other anamnestic data were obtained through interviews. Patients with FC (Pro/Pro = 19.0%, Arg/Arg = 42.9%, Arg/Pro = 38%) and with PC (Pro/Pro = 10.3%, Arg/Arg = 36.36%, Arg/Pro = 53.24%) showed a significant overrepresentation of codon 72 variants compared to the control population (Pro/Pro = 1.9%, Arg/Arg = 33.3%, Arg/Pro = 64.7%) (P = 0.0015). The Pro/Pro genotype, after adjusting for gender, age, tobacco and drugs, was associated with a markedly higher risk of FC (OR=9.714; CI: 2.334-40.436) and of PC (OR=5.299; CI: 2.334-40.436). These results provide evidence that p53 polymorphism is implicated in thyroid carcinogenesis and that individuals harboring the Pro/Pro genotype have an increased risk of developing thyroid cancer.

Asunto(s)

Adenocarcinoma Folicular/genética , Adenoma/genética , Carcinoma Papilar/genética , Genes p53/genética , Predisposición Genética a la Enfermedad , Mutación de Línea Germinal , Polimorfismo Genético , Enfermedades de la Tiroides/genética , Neoplasias de la Tiroides/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Carcinógenos/efectos adversos , Estudios de Casos y Controles , Codón/genética , Femenino , Genotipo , Homocigoto , Humanos , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Prolina/química