How p16 and MC1R mutations synergistically exacerbate melanoma risk.

描述（由申请人提供）：黑皮质素1受体（MC 1 R）和p16 INK 4A（p16）是真正的黑色素瘤易感基因，其中p16突变对风险的影响最大，MC 1 R功能丧失（LOF）变体在黑色素瘤患者和黑色素瘤易感个体中最常见。p16和MC 1 R突变共同遗传的遗传影响得到了令人信服的流行病学证据的支持，但这两种基因相互作用影响黑色素瘤风险的分子机制尚不清楚。早期的研究将它们的综合作用归因于细胞周期失调和DNA修复缺陷。我们的研究小组发现，这两个危险因素共享的分子机制也涉及黑素细胞的抗氧化能力。我们在研究MC 1 R和p16功能方面的丰富经验使我们作为一个团队处于最佳位置，以进一步表征两种基因突变的遗传协同作用导致黑色素瘤风险的机制。使用独特的皮肤细胞原代培养物，包括来自p16和MC 1 R突变患者的黑色素细胞，为我们提供了前所未有的机会，以确定可用于黑色素瘤预防和治疗的新的共同途径。我们提出的假设是，共同遗传的p16和MC 1 R的种系突变导致黑素细胞的抗氧化剂和DNA修复反应的紫外线的协同破坏，这些保护机制的缺陷是黑色素瘤的极高风险的基础上观察到的个人谁携带在这两个基因的突变。该假设将在两个特定目的中进行测试，1）使用培养的黑素细胞和3-D皮肤构建体，评价p16突变和/或MC 1 R RHC变体对p16表达的影响以及在细胞周期和衰老的调节、DNA损伤的修复和氧化应激中的功能，和2）使用RNA测序确定p16和/或MC 1 R突变对UV照射的原代黑素细胞培养物中基因表达的影响。所确定的预防和治疗机会将不仅对为这里提议的工作捐献组织的高危患者产生重大影响，而且对所有有可能感染这一致命疾病的人产生重大影响。

DESCRIPTION (provided by applicant): The melanocortin 1 receptor (MC1R) and p16 INK4A (p16) are bona fide melanoma predisposition genes, with mutations in p16 having the highest impact on risk, and MC1R loss of function (LOF) variants being the most common in melanoma patients and melanoma prone individuals. The genetic impact of co-inheritance of p16 and MC1R mutations is supported by compelling epidemiological evidence, but the molecular mechanisms by which the interaction of these two genes impacts melanoma risk is not well understood. Earlier work has attributed their combined effects to cell cycle deregulation and DNA repair deficiencies. Our team has discovered that these two risk factors share molecular mechanisms that also involve the antioxidant capacity of melanocytes. Our extensive experience in investigating the functions of MC1R and p16 puts us in the best position as a team to further characterize the mechanisms by which inheritance of mutations in both genes synergistically contributes to melanoma risk. Using unique primary cultures of skin cells including melanocytes derived from patients with mutations in both p16 and MC1R provides us with the unprecedented opportunity to identify novel common pathways that can be targeted for melanoma prevention and treatment. We propose the hypothesis that co-inheritance of germline mutations in p16 and MC1R causes synergistic disruption of the antioxidant and DNA repair responses of melanocytes to UV, and deficiencies in these protective mechanisms underlie the extremely high risk for melanoma observed in individuals who carry mutations in both genes. This hypothesis will be tested in two Specific Aims, 1) to evaluate the effects of p16 mutations and/or MC1R RHC variants on p16 expression and function in regulation of the cell cycle and senescence, repair of DNA damage, and oxidative stress, using cultured melanocytes and 3-D skin construct, and 2) to determine the effects of p16 and/or MC1R mutations on gene expression in UV-irradiated primary melanocyte cultures using RNA sequencing. The prevention and treatment opportunities identified will have significant impact not only in the high-risk patients who have donated tissue for the work proposed here, but on all persons at risk for this deadly disease.