Hereditary cancer predisposition syndromes and uveal melanoma

遗传性癌症易感综合征和葡萄膜黑色素瘤

• 批准号: 8814292
• 负责人: Mohamed H. Abdel-Rahman
• 金额: $ 20.1万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-12-08 至 2016-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8814292
• 关键词: 3' Untranslated Regions; Accounting; BRCA1 Associated Protein-1; Cancer Etiology; Candidate Disease Gene; Clinical; Clinical Treatment; Code; Copy Number Polymorphism; Custom; Cutaneous Melanoma; Data; Disease; Disease model; Environmental Risk Factor; Epigenetic Process; Eye; Family; Family history of; Family member; Frequencies; Gene Rearrangement; General Population; Genes; Genetic; Genetic Counseling; Genetic Predisposition to Disease; Genetic screening method; Genetic study; Genome; Germ-Line Mutation; Goals; Health; Healthcare; Hereditary Malignant Neoplasm; Hereditary Neoplastic Syndromes; High-Risk Cancer; Individual; Inherited; Intervention; Laboratories; Lead; Ligation; Malignant Neoplasms; Measures; Medical Genetics; Mesothelioma; Methylation; MicroRNAs; Molecular; Mutation; Nevus; Ocular Melanoma; Online Mendelian Inheritance In Man; Ophthalmic examination and evaluation; Outcome; Pathogenesis; Patient risk; Patients; Phenotype; Predisposition; Promoter Regions; Regulation; Renal carcinoma; Reporting; Risk; Screening for cancer; Southern Blotting; Syndrome; Testing; Tissues; Tumor Tissue; Untranslated Regions; Uveal Melanoma; Variant; Work; base; clinical Diagnosis; clinical phenotype; clinically significant; cohort; deep sequencing; early onset; exome sequencing; follow-up; gene discovery; genetic variant; high risk; mRNA Expression; melanoma; novel; prevent; promoter; screening; segregation; targeted treatment; tumor

DESCRIPTION (provided by applicant): Uveal melanoma (UM) is a subtype of melanoma characterized by the strong contribution of genetic rather than environmental factors in the pathogenesis of the disease, making it an ideal model disease to study the genetic basis of cancer. The long-term goal of our laboratory is to determine the genes and mechanisms responsible for hereditary cancer predisposition associated with UM. To accomplish this, we have collected a large cohort of UM patients with high risk of hereditary cancer predisposition. Our work to date with this cohort supports that germline inactivation of BAP1 and other gene(s), account for the hereditary cancer syndromes in a subset of UM patients. This will be tested with two specific aims, one focused on BAP1 studies and one on other candidate genes: Aim 1: Identify mechanisms of germline BAP1 inactivation in UM patients with clinical phenotype suggestive of tumor predisposition syndrome (TPDS). Aim 2: Identification of novel candidate genes contributing to hereditary predisposition to UM. Scientific and Translational Impact: Outcomes will include identification of molecular mechanisms of heritable germline inactivation in BAP1 in patients with UM. This will provide much needed information for genetic counseling of patients at risk of TPDS, especially now that this gene is being added to clinical genetic testing panels. Identification of additional candidate genes associated with hereditary predisposition to UM will lead to further studies by us and others to further characterize the clinical phenotype and potential targets for therapy of these syndromes

描述(申请人提供)：葡萄膜黑色素瘤(UM)是黑色素瘤的一种亚型，在疾病的发病机制中具有遗传因素而不是环境因素的强烈贡献，使其成为研究癌症遗传基础的理想模型疾病。我们实验室的长期目标是确定与UM相关的遗传性癌症易感性的基因和机制。为了实现这一点，我们收集了一大批具有遗传性癌症易感性的UM患者。到目前为止，我们在这个队列中的工作支持BAP1和其他基因(S)的种系失活，这是UM患者亚群中遗传性癌症综合征的原因。这将以两个特定的目标进行测试，一个集中在BAP1研究上，另一个集中在其他候选基因上：目标1：确定具有肿瘤易感综合征(TPDS)临床表型的UM患者种系BAP1失活的机制。目的2：寻找与UM遗传易感性相关的新候选基因。科学和翻译影响：结果将包括确定UM患者BAP1中可遗传种系失活的分子机制。这将为有TPDS风险的患者提供急需的遗传咨询信息，特别是现在该基因正被添加到临床基因检测小组。识别与UM遗传易感性相关的其他候选基因将导致我们和其他人进一步研究这些综合征的临床表型和潜在的治疗靶点。