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The Genetics of Ocular Melanoma

眼部黑色素瘤的遗传学

基本信息

批准号：
10596996
负责人：
Anne Mary Bowcock
金额：
$ 64.03万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10596996
关键词：
Abnormal Karyotype Address Age Alternative Splicing Antineoplastic Agents Applications Grants Automobile Driving BAP1 gene Biological Models Biological Sciences Blindness Cancer Model Candidate Disease Gene Cell Line Cessation of life Characteristics Chromatin Remodeling Factor Chromosome 3 Chromosome abnormality Chromosomes Classification Clinical Competence Complement DNA Sequence Rearrangement DNA sequencing Detection Development Diagnosis Drosophila genus Epithelium Event Exhibits Eye Eye Neoplasms Future G-Protein-Coupled Receptors GNAQ gene GTP-Binding Proteins Gene Expression Profile Gene Fusion Generations Genes Genetic Genome Genomic DNA Genomics Grant Growth Human Immune checkpoint inhibitor Introns Length Loss of Heterozygosity MEKs Malignant Neoplasms Maps Modeling Molecular Mutation Neoplasm Metastasis Nonmetastatic Ocular Melanoma Oncogenic Orthologous Gene Pathogenicity Pathway interactions Patients Phenotype Primary Neoplasm Prognosis Protein Isoforms RNA Recurrence Research Resolution Risk Signal Transduction Site Solid Neoplasm Somatic Mutation System Systemic Therapy Testing Tissues Transgenic Organisms Up-Regulation Uveal Melanoma Variant Wing Work cancer genome chromatin modification chromosome 1p loss chromosome 8q gain cysteinyl leukotriene receptor 2 driver mutation effective therapy epigenomics exome experimental study fly guanine nucleotide binding protein high risk insight loss of function loss of function mutation malignant neoplasm of eye melanocyte melanoma monolayer novel therapeutics polypeptide single molecule success therapeutic candidate transcriptome sequencing tumor tumor diagnosis

项目摘要

PROJECT SUMMARY/ABSTRACT Uveal melanoma (UM) is the second most common form of melanoma and the most common primary cancer of the eye, resulting not only in vision loss, but in metastatic death in up to half of patients. There are no effective treatment options once the tumor metastasizes and patients usually die within a few months of diagnosis despite systemic therapy. UMs harbor activating oncogenic mutations in GNAQ, GNA11 or CYSLTR2 that occur early in tumor formation and that are unrelated to metastatic risk. We showed that over 80% of class 2 UMs harbor loss of function mutations of BAP1 and that recurrent mutations altering R625 of SF3B1 are found in tumors with slower rates of metastasis. Mutations in EIF1AX are associated with tumors with minimal chance of metastasis. The presence of BAP1, SF3B1 and EIF1AX mutations, are nearly always mutually exclusive. However, overlaid on this are genomic rearrangements that include gain of chromosomes 8q and 6p, and loss of chromosomes 1p, 6q and 8p. Our studies of these karyotypic/copy number alterations in UM have identified a critical chromatin modifier mapping to chromosome 6q (PHF10) and candidate genes in other regions of recurrent chromosomal alteration. The consequences of these changes in the development of UM are poorly understood. To extend and refine our copy number studies we will now will perform long-read single molecule sequencing of DNA and RNA isolated from primary UMs with different driver mutations and CNAs. In Aims 1 and 2 we will perform long-read single molecule sequencing (SMRT) to develop detailed maps of the structural variations (SVs) of the genomes of these tumors, identifying and characterizing critical breakpoints, gene fusions and tumor specific isoforms. Besides obtaining insights into the generation of chromosomal alterations we will validate and refine focal deletions and identify critical isoforms in such regions. Functional analyses in cell lines will examine the consequences of gene fusions and isoforms highly correlated with copy number changes. In parallel and in Aim 3 we will use the power of fly genetics to investigate the consequence of major alterations in UM in D. Melanogaster. We will first generate and characterize flies with loss of function mutations in the BAP1 ortholog calypso, and generate activating mutations of the GNAQ ortholog GαQ so that the combined effect of loss of calypso and activation of GαQ can be investigated. We will focus on larval eye discs and wing discs that represented well-ordered epithelial monolayers and examine the the phenotypic, signaling and epigenomic changes that arise from these mutations. The fly model is capable of addressing the functional relevance of the genomic insights from all three Aims by performing rapid genetic interactions. In the future, candidate UM drivers identified from Aims 1-2 will be tested for the ability to modify the cancer-like phenotypes we see in our two hit GαQ and calypso fly model. Genetic suppressors of overgrowth, tissue transformation, and metastasis phenotypes would represent exciting therapeutic candidates to pursue in future studies.

项目总结/摘要葡萄膜黑色素瘤（UM）是第二种最常见的黑色素瘤形式，也是葡萄膜炎中最常见的原发性癌症。眼睛，不仅导致视力丧失，而且在多达一半的患者中导致转移性死亡。没有有效一旦肿瘤转移，患者通常在诊断后几个月内死亡，全身治疗UM携带GNAQ、GNA 11或CYSLTR 2中的激活致癌突变，这些突变发生在在肿瘤形成中的作用，并且与转移风险无关。我们发现，超过80%的2级UM BAP 1的功能丧失突变和改变SF 3B 1的R625的复发性突变在具有以下特征的肿瘤中发现：转移率更低。EIF 1AX突变与转移机会极小的肿瘤相关。 BAP 1、SF 3B 1和EIF 1AX突变的存在几乎总是相互排斥的。然而，在此基础上是基因组重排，包括染色体8 q和6p的增加，以及染色体1 p的丢失， 6 q和8 p。我们对UM中这些核型/拷贝数改变的研究已经确定了一个关键的染色质修饰子定位到染色体6 q（PHF 10）和复发染色体的其他区域中的候选基因变更。UM发展中这些变化的后果知之甚少。扩展和为了完善我们的拷贝数研究，我们现在将对DNA和RNA进行长读单分子测序，分离自具有不同驱动突变和CNA的原代UM。在目标1和2中，我们将执行长读单分子测序（SMRT），以开发基因组结构变异（SV）的详细图谱这些肿瘤，识别和表征关键断点，基因融合和肿瘤特异性亚型。除了深入了解染色体改变的产生，我们还将验证和完善焦点。缺失并鉴定这些区域中的关键同种型。细胞系的功能分析将检查基因融合和同种型的结果与拷贝数变化高度相关。在平行和目标我们将利用果蝇遗传学的力量来研究D. 黑腹龙我们将首先产生并表征BAP 1直系同源物中具有功能缺失突变的果蝇， calypso，并产生GNAQ直系同源物GαQ的激活突变，使得GNAQ缺失的联合效应。 calypso和GαQ的激活。我们将重点关注幼虫的眼盘和翅盘，代表有序的上皮单层，并检查表型，信号和表观基因组由这些突变引起的变化。苍蝇模型是能够解决的功能相关性通过执行快速遗传相互作用，从所有三个目标中获得基因组见解。将来，候选UM驱动程序我们将测试从目标1-2中鉴定出的两种基因修饰癌症样表型的能力， GαQ和卡里普索蝇模型。过度生长、组织转化和转移的遗传抑制因子表型将代表令人兴奋的治疗候选者，以在未来的研究中进行。