OBJECTIVES: The aim of this study was to examine the expression of the N-myc downstream-regulated gene 1 protein in benign and malignant lesions of the thyroid gland by immunohistochemistry. INTRODUCTION: N-myc downstream-regulated gene 1 encodes a protein whose expression is induced by various stimuli, including cell differentiation, exposure to heavy metals, hypoxia, and DNA damage. Increased N-myc downstream-regulated gene 1 expression has been detected in various types of tumors, but the role of N-myc downstream-regulated gene 1 expression in thyroid lesions remains to be determined. METHODS: A tissue microarray paraffin block containing 265 tissue fragments corresponding to normal thyroid, nodular goiter, follicular adenoma, papillary thyroid carcinoma (classical pattern and follicular variant), follicular carcinoma, and metastases of papillary and follicular thyroid carcinomas were analyzed by immunohistochemistry using a polyclonal anti- N-myc downstream-regulated gene 1 antibody. RESULTS: The immunohistochemical expression of N-myc downstream-regulated gene 1 was higher in carcinomas compared to normal thyroid glands and nodular goiters, with higher expression in classical papillary thyroid carcinomas and metastases of thyroid carcinomas (P < 0.001). A combined analysis showed higher immunohistochemical expression of NDRG1 in malignant lesions (classical pattern and follicular variant of papillary thyroid carcinomas, follicular carcinomas, and metastases of thyroid carcinomas) compared to benign thyroid lesions (goiter and follicular adenomas) (P = 0.043). In thyroid carcinomas, N-myc downstream-regulated gene 1 expression was significantly correlated with a more advanced TNM stage (P = 0.007) and age, metastasis, tumor extent, and size (AMES) high-risk group (P = 0.012). CONCLUSIONS: Thyroid carcinomas showed increased immunohistochemical N-myc downstream-regulated gene 1 expression compared to normal and benign thyroid lesions and is correlated with more advanced tumor stages.

Acute intermittent porphyria (AIP, OMIM 176000) is an autosomal dominant metabolic disease caused by mutations in the gene encoding hydroxymethylbilane synthase (HMBS; EC 4.3.1.8; formely named porphobilinogen deaminase, PBGD), mapped to chromosome 11q23.3. We describe a novel mutation of the HMBS gene, a de novo 3-base deletion in the splicing donor site of intron 3 (IVS3+2_4delTGG) in a woman affected by AIP. RT-PCR analysis revealed an abnormal HMBS mRNA, compatible with exon 3 skipping.

CONTEXTO: Mutações nos genes ras têm sido associadas a diversos tumores sólidos humanos. Membros da família de genes ras (Ki-ras, Ha-ras e N-ras) são estruturalmente relacionados e codificam para uma proteína (p21) que desempenha papel importante na regulação da transdução de sinal e crescimento celular.OBJETIVOS: Estudar a ocorrência de mutações nos genes Ki-ras e Ha-ras. Também estudamos a expressão do gene Ha-ras em 32 dos tumores de cabeça e pescoço. TIPO DE ESTUDO: Série de casos.PARTICIPANTES: 60 tumores de cabeça e pescoço e 28 nasoangiofibromas obtidos através de cirurgia.LOCAL: Hospital A. C. Camargo e Hospital das Clínicas da Universidade de São Paulo, respectivamente.TESTE DIAGNÓSTICO: Pela técnica de PCR-SSCP examinamos a ocorrência de mutações nos genes Ki-ras e Ha-ras. O nível relativo do mRNA de Ha-ras em 32 dos tumores de cabeça e pescoço foi examinado por Northern blot. RESULTADOS: Nenhum dos tumores de cabeça e pescoço nem os nasoangiofibromas apresentaram evidência de mutação nos codons 12, 13, 59 e 61 dos genes Ki-ras e Ha-ras; contudo, 17 (53%) dos tumores, onde a expressão gênica pode ser examinada, demonstraram níveis aumentados do mRNA de Ha-ras quando comparados com o tecido normal do mesmo paciente.CONCLUSÕES: Nossos resultados demonstram, pela primeira vez, que mutações nos genes Ki-ras e Ha-ras não estão associadas ao desenvolvimento dos nasoangiofibromas e confirmam trabalhos anteriores que demonstram que mutações que ativam o gene ras estão ausentes ou raramente associadas aos tumores de cabeça e pescoço de pacientes ocidentais. Além disso, nossos resultados sugerem que o aumento de expressão de Ha-ras, e não a mutação desse gene, possa ser um fator importante no desenvolvimento e progressão dos tumores de cabeça e pescoço.

CONETXT: Ras gene mutations have been associated to a wide range of human solid tumors. Members of the ras gene family (Ki-ras, Ha-ras and N-ras) are structurally related and code for a protein (p21) known to play an important role in the regulation of normal signal transduction and cell growth. The frequency of ras mutations is different from one type of tumor to another, suggesting that point mutations might be carcinogen-specific. OBJECTIVES: To study the occurrence of Ki-ras and Ha-ras mutations. We also studied the relative level of Ha-ras mRNA in 32 of the head and neck tumors. DESIGN: Case series. SETTING: University referral unit. PARTICIPANTS: 60 head and neck tumors and in 28 Juvenile Nasopharyngeal Angiofibromas (JNA). DIAGNOSTIC TEST: Using PCR-SSCP we examined the occurrence of Ki-ras and Ha-ras mutations. The relative level of Ha-ras mRNA was examined by Northern blot analysis. RESULTS: None of the head and neck tumors or JNA samples showed evidence of mutations within codons 12, 13, 59 and 61 of Ki-ras or Ha-ras genes. However, 17 (53%) of the tumors where gene expression could be examined exhibited increased levels of Ha-ras mRNA compared with the normal tissue derived from the same patient. CONCLUSIONS: Our results demonstrate for the first time that mutations of Ki-ras and Ha-ras genes are not associated with the development of JNA and confirm previous reports indicating that activating ras mutations are absent or rarely involved in head and neck tumors from western world patients. Furthermore, our findings suggest that overexpression of Ha-ras, rather than mutations, might be an important factor in the development and progression of head and neck tumors.