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，大大增加了对预防和治疗方法的需求。有证据表明，趋化因子及其受体是许多癌症（包括黑色素瘤）中肿瘤免疫、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证明是由多态性改变，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一个单一的趋化因子受体的多态性，影响黑色素瘤的风险，但尚未全面调查黑色素瘤和趋化因子或趋化因子受体多态性之间的联系已经进行。我们建议详细说明趋化因子及其受体的遗传变异，并在大型国际人群为基础的基因，环境和黑色素瘤（GEM）研究中确定其与黑色素瘤风险，生存率，NRAS和BRAF突变亚型的相关性。我们还将确定这些关系是否会受到年龄、紫外线暴露、表型性状和其他基因多态性的影响。以前很少有研究同时解决了黑色素瘤的“免疫原性”沿着致癌途径。这些结果可能会改善环境保护的风险预测和循证建议，并为受影响的患者提供更好的结果预测和定制治疗模式。 公共卫生相关性： 这种竞争性更新的目的是确定趋化因子及其受体的遗传变异体（肿瘤免疫的关键调节剂）是否与黑色素瘤风险、生存率和黑色素瘤中的肿瘤突变相关，特别关注风险的协变量：年龄和紫外线辐射。这项工作将在一项针对3,000多名黑色素瘤患者的大型国际人群研究的背景下进行。这些结果应该导致更好的风险预测和更多基于证据的环境保护建议，并能够更好地预测生存率，并确定最有可能从黑色素瘤靶向治疗中受益的患者群体。

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. PUBLIC HEALTH RELEVANCE: The objective of this competitive renewal is to determine whether inherited variants of chemokines and their receptors, which are key modulators of tumor immunity, are associated with melanoma risk, survival, and tumor mutations in melanoma, with a particular focus on covariates of risk: age and ultraviolet radiation. The work will be done in the context of a large international population-based study of over 3,000 melanoma patients. The results should lead to better risk prediction and more evidence-based recommendations for environmental protection and enable better survival prediction and the identification of patient groups most likely to benefit from targeted therapies for melanoma treatment.