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，这些转移通常对药物治疗有抗药性。此外，黑色素瘤的发病率和死亡率正在上升，这大大增加了对预防和治疗方法的需求。有证据表明，趋化因子及其受体在包括黑色素瘤在内的许多癌症中是肿瘤免疫、进展、转移和血管生成的重要调节因子。趋化因子及其受体的活性已被多态性所改变，但这些变化对黑色素瘤的影响仍有待阐明。初步工作已经确定了影响黑色素瘤风险的单一趋化因子受体的多态性，但尚未对黑色素瘤与趋化因子或趋化因子受体多态性之间的联系进行全面调查。我们建议在大型国际人群基因、环境和黑色素瘤（GEM）研究中详细介绍趋化因子及其受体的遗传变异，并确定它们与黑色素瘤风险、生存以及NRAS和BRAF突变亚型的关系。我们还将确定这些关系是否受到年龄、紫外线照射、表型特征和其他基因多态性的影响。以前很少有研究同时研究黑色素瘤的“免疫原性”和致癌途径。该结果可能会改善风险预测和基于证据的环境保护建议，并为受影响患者提供更好的结果预测和定制治疗范例。

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 and treatment. Evidence suggests that chemokines and their receptors are important regulators of tumor immunity, progression, metastasis, and, angiogenesis in many cancers, including melanoma. The activities of chemokines and their receptors have been shown to be altered by polymorphisms but the impact of these changes on melanoma remains to be elucidated. Preliminary work has identified a polymorphism of a single chemokine receptor that influences the risk of melanoma, but as yet no comprehensive investigations of links between melanoma and chemokine or chemokine receptor polymorphisms have been performed. We propose to detail inherited variations in chemokines and their receptors and determine their associations with melanoma risk, survival, and NRAS and BRAF mutational subtypes in the large international population-based Genes, Environment, and Melanoma (GEM) study. We will also determine whether these relationships are modified by age, ultraviolet exposure, phenotypic traits, and polymorphisms in other genes. Few previous studies have simultaneously addressed the 'immunogenicity' of melanoma along with the oncogenic pathways. The results are likely to improve risk prediction and evidence-based recommendations for environmental protection and enable better outcomes prediction and customization of treatment paradigms for affected patients.