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Telomere dysfunction and genome instability in familial melanoma

家族性黑色素瘤的端粒功能障碍和基因组不稳定性

基本信息

批准号：
9196338
负责人：
Sandy S Chang
金额：
$ 21.86万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-12-16 至 2018-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9196338
关键词：
Address Alleles American Apoptosis Benign Biological Assay Bypass CDKN2A gene Cell Proliferation Characteristics Chromosome abnormality Combined Modality Therapy Complex Cutaneous Melanoma DNA DNA Damage DNA Ligation DNA Repair DNA Repair Pathway DNA Sequence Rearrangement Early Diagnosis Family Functional disorder Gene Order Genes Genetic Genome Stability Genomic Instability Germ-Line Mutation Growth Health Hereditary Melanoma Human Incidence Inherited Lead Lesion Maintenance Malignant Neoplasms Mediating Monitor Mutate Mutation Nevi and Melanomas Nevus Nonhomologous DNA End Joining Oncogenes Oncogenic Pathway interactions Penetrance Pharmaceutical Preparations Play Population Proteins Recruitment Activity Recurrence Reporting Role Sampling Somatic Mutation Structural Chromosomal Abnormality TP53 gene Telomerase Telomere Maintenance Telomere-Binding Proteins Testing Transcript Tumor Necrosis Factor Ligand Superfamily Member 6 Xenograft procedure advanced disease chromosome fusion disorder risk ds-DNA fusion gene genomic profiles high risk loss of function melanoma mouse model mutant next generation sequencing novel permissiveness prevent promoter public health relevance reconstitution repaired response senescence telomere transcriptome sequencing tumor tumor progression tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Familial melanomas comprise 10% of all melanomas. A characteristic feature of melanomas is their strikingly complex genomic profiles, highlighted by genomic rearrangements and chromosome structural aberrations. However, mechanisms responsible for the chromosomal alterations that potentially drive tumorigenesis remain unclear. We postulate that melanomas with mutations disrupting the function of the Protection of Telomere 1 (POT1) protein depend upon the alternative, Lig4-independent NHEJ (A-NHEJ) pathway for DNA repair. We will use mouse models and human tumor samples to understand how progressive telomere dysfunction and activation of the A-NHEJ pathway generate pro-oncogenic chromosomal aberrations and the stepwise accumulation of mutational changes in favor of melanoma initiation and progression.

描述（由申请人提供）：家族性黑色素瘤占所有黑色素瘤的10%。黑色素瘤的一个典型特征是其惊人的复杂基因组谱，突出表现为基因组重排和染色体结构畸变。然而，可能驱动肿瘤发生的染色体改变的机制仍不清楚。我们假设，黑色素瘤的突变破坏端粒1（POT 1）蛋白的保护功能取决于替代的，Lig 4-独立的NHEJ（A-NHEJ）的DNA修复途径。我们将使用小鼠模型和人类肿瘤样本来了解进行性端粒功能障碍和A-NHEJ通路的激活如何产生促癌染色体畸变以及突变变化的逐步积累，从而有利于黑色素瘤的发生和进展。