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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：
8702554
负责人：
Anne Mary Bowcock
金额：
$ 38.55万
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 2016-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8702554
关键词：
Automobile Driving BARD1 gene BRCA1 Associated Protein-1 BRCA1 gene BRCA2 gene Binding Binding Proteins Biological Assay Blood Cancer Etiology Cell Line Cellular Morphology Cessation of life Characteristics Chromosomes, Human, Pair 3 Classification Clinical Code Cytogenetics DNA DNA Sequence Development Diagnosis Diagnostic Dideoxy Chain Termination DNA Sequencing Disease Eye Neoplasms Frequencies Gene Expression Gene Expression Profile Gene Mutation Genes Genetic Genomic Instability Genomics Goals Lead Liver Malignant Neoplasms Maps 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 breast neoplasm 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：转移是恶性肿瘤的一个重要特征，也是癌症相关死亡的最常见原因。然而，转移的遗传学却知之甚少。葡萄膜黑色素瘤是最常见的原发性眼癌，是第二种最常见的黑色素瘤。UM具有高度的特点对常规化疗耐药的肝脏转移模式，通常是致命的。UMS有非常少的基因组不稳定，很少的细胞遗传学改变，以及罕见的基因突变。因此，当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 可根据转移死亡的风险分为1类(低风险)和2类(高风险)，基于经过验证的基因表达签名。研究的一个主要焦点一直是识别特定的基因 UM中授予转移性能力的变化。第二类签名通常伴随着丢失 3号染色体的一个拷贝(单体3)，这导致了人们普遍预期一个拷贝的丢失 UM细胞中3号染色体的突变揭示了剩余的一个或多个基因中的隐性失活突变具有转移能力的3号染色体的拷贝。其他变化包括8q染色体的获得和染色体8p丢失。在1类肿瘤中，染色体6p的获得是常见的。调查人员) 这一建议是UM分子遗传学分析的先驱。我们是第一个申请的团体最近描述的外显子组捕获和大规模并行测序鉴定BAP1的技术作为UM中3号染色体的转移抑制基因。在目前的研究中，我们将利用我们的最近利用这些技术成功地识别了更多的肿瘤抑制基因和突变的癌基因在UM。在目标1中，我们将生成1类和2类肿瘤的额外外显子序列，比较他们有相匹配的生殖系DNA。潜在的肿瘤抑制基因含有有害突变，而含有潜在激活突变的癌基因将被证实为UM的发展在另外10-30个1-30个1-2类肿瘤和匹配的种系中进行Sanger测序和评估 DNA在目标2中，我们将使用定向捕获来对新发现的这些基因中的其他突变进行重新排序其他样本(每种肿瘤类型的100个)中的基因，以确定它们对UM的贡献。在《目标3》中，我们将对细胞系中新发现的5个基因进行有限的功能研究。我们将进行约束性分析以评估错义和帧内编码更改对与已知和新伙伴的交互的影响，过表达激活癌基因和敲除肿瘤抑制基因以确定它们对细胞的影响形态和基因表达。关于肿瘤分子变化的信息将被合并到临床资料开始制定UM的预后分类。这是一份来自来自眼科和遗传科的多学科协作小组已经证明完成这项提案的目标所需的专业知识。)