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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：
8826698
负责人：
Anne Mary Bowcock
金额：
$ 40.38万
依托单位：
IMPERIAL COLLEGE OF SCIENCE, TECHNOLOGY AND MEDICINE
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 2017-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8826698
关键词：
Automobile Driving BARD1 gene BRCA1 Associated Protein-1 BRCA1 gene BRCA2 gene Binding Binding Proteins Biological Assay Blood Breast Cancer gene Cancer Etiology Cell Line Cellular Morphology Cessation of life Characteristics Chromosomes, Human, Pair 3 Classification Clinical Code Cytogenetics DNA DNA Sequence DNA Sequence Alteration Development Diagnosis Diagnostic Dideoxy Chain Termination DNA Sequencing Disease Eye Neoplasms Frequencies Gene Expression Gene Expression Profile Genes Genetic Genomic Instability Genomic Segment Genomic approach Goals Lead Liver Malignant Neoplasms Maps Massive Parallel Sequencing Melanoma Cell Metastatic Neoplasm to the Liver Methods Molecular Molecular Genetics Monosomy Mutate Mutation Neoplasm Metastasis Ocular Melanoma Oncogenes Oncogenic Oncologist Ophthalmology Outpatients Pathway interactions Patients Pattern Protein Isoforms Research Research Personnel Resistance Retinoblastoma Risk Role Sampling Science Somatic Mutation Susceptibility Gene Techniques Technology Tertiary Protein Structure Tumor Suppressor Genes Tumor Suppressor Proteins Uveal Melanoma Work abstracting base cancer risk chemotherapy chromosome 6p gain chromosome 8p loss chromosome 8q gain early onset exome exome sequencing expectation follow-up high risk insight malignant neoplasm of eye melanoma multidisciplinary novel personal narratives prognostic screening success tumor tumorigenesis

项目摘要

Abstract: Metastasis is a defining feature of malignant tumors and is the most common cause of cancer-related death. However, the genetics of metastasis are poorly understood. Uveal melanoma (UM) is the most common primary cancer of the eye and the second most common form of melanoma. UMs have a highly characteristic pattern of metastasis to the liver that is resistant to conventional chemotherapy and is usually fatal. UMs have remarkably little genomic instability, few cytogenetic alterations, and rare genetic mutations. Thus, when mutations are found in these tumors, they are highly likely to be driver rather than passenger mutations. UMs can be grouped according to risk of metastatic death into class 1 (low risk) and class 2 (high risk) based on a validated gene expression signature. A major focus of research has been to identify the specific genetic changes that confer metastatic competency in UM. The class 2 signature is usually accompanied by loss of one copy of chromosome 3 (monosomy 3), which has led to the widespread expectation that loss of one copy of chromosome 3 in UM cells unmasks recessive inactivating mutations in a gene (or genes) on the remaining copy of chromosome 3 that confer metastatic capacity. Other changes include gain of chromosome 8q and loss of chromosome 8p. In the class of class 1 tumors, gain of chromosome 6p is common. The)investigators of this proposal are pioneers in the analysis of the molecular genetics of UM. We were the first group to apply the recently described technique of exome capture followed by massively parallel sequencing to identify BAP1 as the metastasis suppressor mapping to chromosome 3 in UM. In the current study we will capitalize on our recent success with these technologies to identify additional tumor suppressor genes and oncogenes mutated in UM. In Aim 1 we will generate additional exome sequences of both class 1 and class 2 tumors, comparing them with their matched germline DNA. Potential tumor suppressor genes harboring deleterious mutations, and oncogenes harboring potential activating mutations driving the development of UM will be confirmed with Sanger sequencing and evaluated in an additional 10-30 class 1 and class 2 tumors and matched germline DNA. In Aim 2 we will use targeted capture to re-sequence newly identified additional mutations within these genes in additional samples (>100 of each tumor type) to determine their contribution to UM. In Aim 3 we will perform limited functional studies of 5 newly identified genes in cell lines. We will perform binding assays to evaluate the effects of mis-sense and in-frame coding changes on interactions with known and novel partners, and over-express activating oncogenes and knockdown tumor suppressors to determine their effect on cell morphology and gene expression. Information on molecular alterations in tumors will then be incorporated with clinical information to begin to develop a prognostic classification of UM. This is a collaborative proposal from a multidisciplinary collaborative group from the departments of Ophthalmology and Genetics that has the proven expertise to complete the aims of this proposal. )

摘要：转移是恶性肿瘤的定义特征，并且是癌症相关死亡的最常见原因。然而，转移的遗传学知之甚少。葡萄膜黑色素瘤（UM）是最常见的原发性眼癌和第二种最常见的黑色素瘤。UM具有高度的特征转移到肝脏的模式，对常规化疗有抵抗力，通常是致命的。UMS有非常少的基因组不稳定性，很少的细胞遗传学改变和罕见的基因突变。因此当如果在这些肿瘤中发现突变，它们很可能是驱动突变而不是乘客突变。UMS 可根据转移性死亡的风险分为1类（低风险）和2类（高风险），验证的基因表达签名。研究的一个主要焦点是确定特定的遗传在UM中赋予转移能力的变化。第2类签名通常伴随着 3号染色体的一个拷贝（3号单体），这导致了广泛的预期， UM细胞中3号染色体的突变揭示了其余染色体上一个基因（或多个基因）的隐性失活突变， 3号染色体的拷贝，赋予转移能力。其他变化包括染色体8 q的增加，染色体8 p缺失。在1类肿瘤中，染色体6p的获得是常见的。调查人员是UM分子遗传学分析的先驱。我们是第一批申请的最近描述的外显子组捕获技术，随后进行大规模平行测序以鉴定BAP 1，作为转移抑制基因定位于UM的3号染色体。在目前的研究中，我们将利用我们的这些技术最近成功地鉴定了额外的肿瘤抑制基因和突变的癌基因在UM。在目标1中，我们将产生1类和2类肿瘤的额外外显子组序列，他们的生殖细胞DNA匹配。携带有害突变的潜在肿瘤抑制基因，携带驱动UM发展的潜在激活突变的癌基因将被证实，桑格测序并在另外10-30个1类和2类肿瘤和匹配的种系中进行评价 DNA.在目标2中，我们将使用靶向捕获来重新测序这些突变中新鉴定的额外突变。基因在额外的样品（>100的每种肿瘤类型），以确定其对UM的贡献。在目标3中，对细胞系中5个新鉴定的基因进行有限的功能研究。我们将进行结合试验，评估错义和框内编码变化对与已知和新伴侣相互作用的影响，并过度表达激活癌基因和敲低肿瘤抑制因子，以确定它们对细胞的影响。形态学和基因表达。然后将肿瘤分子改变的信息与临床信息开始发展UM的预后分类。这是一个合作提案，来自眼科和遗传学部门的多学科合作小组，专业知识，以完成这项建议的目的。)