Melanoma RAS/BRAF Mutation--Heterogeneity-Risk-Prognosis

描述（由申请人提供）：黑色素瘤可以在早期转移，并且这些转移通常对药物治疗有抵抗力。此外，黑色素瘤的发病率和死亡率正在上升，大大增加了对预防、早期诊断和治疗方法的需求。原发性人皮肤黑色素瘤在其进展早期通常在NRAS或BRAF中具有激活突变;这些激活突变在黑色素瘤发展中可能具有因果关系而不是简单的相关作用;并且存在证据支持紫外线与基因型和相关表型易感性结合在黑色素瘤体细胞突变的发病机制中。我们建议在一个大型国际队列中确定黑色素瘤中NRAS和BRAF体细胞突变的基于人群的频率，以及它们与黑色素瘤组织学亚型、已知风险因素和预后指标的相关性。此外，我们将确定第二原发性黑色素瘤患者的肿瘤是否表现出与第一原发性黑色素瘤相似的分子分类。NRAS和BRAF突变状态将使用激光捕获显微镜和单链构象多态性分析与PCR产物直接手动测序的高灵敏度组合进行表征。了解这些体细胞突变在黑色素瘤病因学和进展中的作用可能对其预防，改善诊断和有效应用新的临床治疗至关重要。

DESCRIPTION (provided by applicant): Melanoma can metastasize at an early stage, and these metastases are typically resistant to medical treatment. In addition, melanoma is rising in incidence and mortality, greatly increasing the need for methods of prevention, early diagnosis, and treatment. Primary human cutaneous melanoma often has activating mutations in either NRAS or BRAF early in its progression; these activating mutations likely have a causal rather than simply correlative role in melanoma development; and evidence exists to support ultraviolet, in combination with genotypic and associated phenotypic susceptibilities, in the pathogenesis of somatic mutations in melanoma. We propose to determine the population-based frequencies of NRAS and BRAF somatic mutations in melanomas in a large international cohort and their associations with histologic subtypes, known risk factors, and prognostic indicators in melanoma. In addition, we will determine whether tumors from patients with second primary melanoma exhibit similar molecular classifications to the first primary. NRAS and BRAF mutational status will be characterized using a highly sensitive combination of laser capture microscopy and single strand conformational polymorphism analysis with direct manual sequencing of PCR products. Understanding of the role of these somatic mutations in the etiology and progression of melanoma likely will be crucial for its prevention, improved diagnosis, and effective application of new clinical treatments.