RESUMO
PURPOSE: Activation of proto-oncogenes and inactivation of tumour suppressor genes are the major genetic alterations involved in carcinogenesis. The increase in methylation at the promoter region of a tumour suppressor gene can lead to gene inactivation, selecting cells with proliferative advantage. Thus, promoter hypermethylation is considered a marker in a variety of malignant tumours, including oral cavity. EXPERIMENTAL DESIGN: The methylation pattern of eight genes was evaluated in 40 oral cavity squamous cell carcinomas (OSCCs) and 40 saliva samples from healthy individuals by Q-MSP. Different combinations of genes were also assessed in order to identify gene panels that could better distinguish between OSCC and saliva samples. RESULTS: CCNA1, DAPK, DCC and TIMP3 methylation were highly specific for being found in the OSCC samples. Moreover, the combination of these genes improved detection when compared with single markers, reaching values of 92.5% for sensitivity and specificity (when using the panel CCNA1, DCC, TIMP3). Moreover, DAPK, DCC and TIMP3 were hypermethylated in nearly 90% of clinically T1 and T2 cases. CONCLUSION: The pursuing of this panel of hypermethylated genes is an important tool for the detection of individuals with OSCC. Moreover, the identification of these markers in early stages of OSCC shows the feasibility of using the panel on saliva as possible biomarkers for early diagnosis. The lack of association between the methylation status of these genes and clinical characteristics shows that they are able to distinguish OSCC cases irrespective of social and clinical factors (gender, age, human papillomavirus (HPV) status, clinical stage, vascular embolisation and perineural invasion).
Assuntos
Biomarcadores Tumorais/genética , Carcinoma de Células Escamosas/genética , Metilação de DNA , Epigênese Genética , Testes Genéticos/métodos , Neoplasias de Cabeça e Pescoço/genética , Neoplasias Bucais/genética , Adulto , Idoso , Brasil , Estudos de Casos e Controles , Ciclina A1/genética , Receptor DCC , Proteínas Quinases Associadas com Morte Celular/genética , Estudos de Viabilidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Regiões Promotoras Genéticas , Receptores de Superfície Celular/genética , Reprodutibilidade dos Testes , Carcinoma de Células Escamosas de Cabeça e Pescoço , Inibidor Tecidual de Metaloproteinase-3/genética , Proteínas Supressoras de Tumor/genéticaRESUMO
Head and neck cancer is a collective term that describes malignant tumors of the oral cavity, pharynx, and larynx characterized by high incidence and mortality rates. Although most HNSCC originate from the mucosal surface of the upper aerodigestive tract, where they can be easily detected during a routine clinical examination. Often the definitive diagnosis is delayed because of the difficulty in differentiating from other similar lesions. Activation of proto-oncogenes and inactivation of tumor suppressor genes are the major molecular alterations involved in carcinogenesis. In addition, epigenetic changes can alter the expression of critical genes important in the development of a variety of cancers. The detection of aberrant gene promoter methylation as a tool for the detection of tumors or its use as prognostic marker have been described for many different cancers including HNSCC. The search for biomarkers has as its main aim the evaluation and measurement of the status of normal and pathological biological processes as well as pharmacological responses to certain treatments. The tracking of these biomarkers is an important part for the identification of individuals in the early stages of head and neck cancer for its diagnostic and prognostic relevance reflecting in high survival rates, better quality of life and less cost to the healthcare system. Therefore, assuming that cancer results from genetic and epigenetic changes, analyzes based on gene methylation profile in combination with the pathological diagnosis would be useful in predicting the behavior of these head and neck tumors.