RAS/BRAF Melanoma Mutations: Precursors, Risk, Prognosis

描述（由申请人提供）： 黑色素瘤具有固有的转移易感性，并且通常对药物治疗具有抗性。由于这种潜在致命性疾病的负担日益增加，预计黑色素瘤的预防、早期诊断和治疗的改进方法将变得越来越重要。在相当大比例的原发性侵袭性黑色素瘤中发现了癌基因BRAF和NRAS的体细胞突变。尽管最近在鉴定这些突变方面取得了进展，但其在黑色素瘤中基于人群的频率仍然未知，并且在关于其与黑色素瘤异质性、前驱病变、风险和预后的相关性的知识库中存在关键差距。在这项研究中，将在北卡罗来纳州于2000年首次诊断的300例侵袭性原发性黑色素瘤的连续病例中确定原发性人黑色素瘤中NRAS和BRAF突变的基于人群的频率和突变谱。为这些病例汇编的详细流行病学和病理学信息将允许确定NRAS和BRAF突变表型与组织学亚型、潜在前驱病变、预后指标和风险因素的关联。将使用单链构象多态性分析的高灵敏度技术结合PCR产物的直接手动测序来检测和表征NRAS和BRAF体细胞突变。本研究获得的数据有望阐明NRAS和BRAF在黑色素瘤发生、进展和异质性中的作用，从而更好地预防、早期发现、分类和治疗该疾病。阐明这些突变如何与环境和遗传因素发生关系，应该会导致更多基于证据的风险因素避免建议。此外，了解突变是如何与前体发生关系的，应提供有关应去除哪些潜在前体的信息，并深入了解早期检测方法。这项研究也有望导致新的化疗靶点的鉴定和最近开发的NRAS和BRAF信号传导抑制剂的更有效测试。

DESCRIPTION (provided by applicant): Melanoma has an intrinsic susceptibility to metastasize and is generally resistant to medical treatment. Because of the increasing burden of this potentially lethal disease, improved methods of prevention, early diagnosis and treatment of melanoma are expected to be of increasing importance. Somatic mutations in the oncogenes BRAF and NRAS have been found in a substantial proportion of primary invasive melanomas. Despite recent progress in identification of these mutations, their population-based frequency in melanoma is still unknown and a critical gap exists in the knowledge base regarding their association with heterogeneity, precursor lesions, risk, and prognosis in melanoma. In this study, the population-based frequency and mutational spectrum of NRAS and BRAF mutations in primary human melanoma will be determined in 300 consecutive cases of invasive primary melanoma with first diagnosis in the year 2000 in North Carolina. Detailed epidemiologic and pathology information compiled for these cases will allow the determination of the association of NRAS and BRAF mutational phenotypes with histologic subtype, potential precursor lesions, prognostic indicators and risk factors. NRAS and BRAF somatic mutations will be detected and characterized using the highly sensitive technique of single strand conformational polymorphism analysis combined with direct manual sequencing of PCR products. The data derived from this study is expected to clarify the role of NRAS and BRAF in the development, progression and heterogeneity of melanoma, leading to better prevention, early detection, classification and treatment of this disease. Elucidation of how these mutations might arise in relationship to environmental and hereditary factors should result in more evidence-based recommendations for risk factor avoidance. In addition, understanding how mutations arise in relationship to precursors should provide information regarding which potential precursors should be removed and insight into methods of early detection. This study is also expected to lead to identification of new chemotherapeutic targets and more efficient testing of inhibitors for NRAS and BRAF signaling, which have recently been developed.