How p16 and MC1R mutations synergistically exacerbate melanoma risk.

p16 和 MC1R 突变如何协同加剧黑色素瘤风险。

基本信息

批准号：
8652005
负责人：
ZALFA ABDEL-MALEK
金额：
$ 21.88万
依托单位：
UNIVERSITY OF CINCINNATI
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-03-13 至 2016-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8652005
关键词：
3-Dimensional Age of Onset Agonist Alleles Antioxidants Apoptosis Autologous Binding Biological Assay Biopsy CDKN2A gene Categories Caucasians Caucasoid Race Cell Aging Cell Cycle Arrest Cell Cycle Checkpoint Cell Cycle Deregulation Cell Cycle Regulation Cells Code Country Cyclin-Dependent Kinase 4 DNA DNA Repair DNA Repair Disorder Data Disease Enzymes Epidemiologic Studies Epidemiology Fibroblasts Gene Chips Gene Expression General Population Genes Genetic Genetic Polymorphism Geographic Locations Germ-Line Mutation Goals Hair Color Hereditary Melanoma Human Immunohistochemistry Individual Laboratories Lesion Measures Mediating Melanocortin 1 Receptor Melanocyte stimulating hormone Molecular Mus Mutation Oxidative Stress Pathway interactions Patients Penetrance Persons Pigmentation physiologic function Population Positioning Attribute Prevention Production Proteins Pyrimidine Dimers RNA Sequences Reactive Oxygen Species Regulation Reporting Risk Risk Factors S Phase Skin Skin tanning Susceptibility Gene Syndrome Testing Tissues Tumor Suppressor Proteins UV induced Variant Western Blotting Work base carcinogenesis eumelanin experience genetic variant high risk interest keratinocyte lifetime risk loss of function melanocyte melanoma mutant novel oxidative DNA damage pheomelanin public health relevance receptor coupling repaired response senescence transcription factor ultraviolet irradiation

项目摘要

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.

描述（由申请人提供）：黑皮质素 1 受体 (MC1R) 和 p16 INK4A (p16) 是真正的黑色素瘤易感基因，p16 突变对风险影响最大，MC1R 功能丧失 (LOF) 变异影响最大常见于黑色素瘤患者和黑色素瘤易感人群。 p16 和 MC1R 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，但这两个基因的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影响归因于细胞周期失调和 DNA 修复缺陷。我们的团队发现这两个危险因素具有共同的分子机制，也涉及黑素细胞的抗氧化能力。我们在研究 MC1R 和 p16 功能方面拥有丰富的经验，这使我们作为一个团队处于最佳位置，可以进一步确定这两个基因突变遗传协同增加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 MC1R 突变患者的黑色素细胞，为我们提供了前所未有的机会来识别可用于黑色素瘤预防和治疗的新的共同途径。我们提出这样的假设：p16 和 MC1R 种系突变的共同遗传会导致黑色素细胞对紫外线的抗氧化和 DNA 修复反应的协同破坏，而这些保护机制的缺陷是携带突变的个体中观察到的极高黑色素瘤风险的基础。两个基因。该假设将在两个具体目标中进行测试，1) 使用培养的细胞评估 p16 突变和/或 MC1R RHC 变体对 p16 表达和功能在细胞周期和衰老调节、DNA 损伤修复和氧化应激中的影响。黑素细胞和 3-D 皮肤构建体，以及 2) 使用 RNA 测序确定 p16 和/或 MC1R 突变对紫外线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不仅对为本文提议的工作捐赠组织的高危患者产生重大影响，而且对所有面临这种致命疾病风险的人产生重大影响。