Discovery and Pathogenetic Significance of Chromosome Translocations in Angiosarcom

血管肉瘤染色体易位的发现及其致病意义

• 批准号: 9187985
• 负责人: JAIME F. MODIANO
• 金额: $ 7.62万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-12-01 至 2018-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9187985
• 关键词: Address; Affect; Anatomy; Biology; Blood Vessels; Canis familiaris; Cells; Characteristics; Chromosomal translocation; Chromosome abnormality; Chronic Myeloid Leukemia; Classification; Clinical; Communities; Complex; Computer software; Custom; Data; Data Set; Development; Diagnosis; Disease; Disease Progression; Dog Diseases; Event; Fluorescent in Situ Hybridization; Frequencies; Gene Expression; Gene Expression Profile; Gene Expression Profiling; Genes; Genome; Genomics; Hemangiosarcoma; Heterogeneity; Human; Inflammatory; Investigational New Drug Application; Legal patent; Malignant Neoplasms; Mammals; Mediating; Methods; MicroRNAs; Modeling; Molecular; Morphology; Natural History; Non-Malignant; Pathogenesis; Pathology; Pathway interactions; Patients; Process; Property; Public Domains; Recurrence; Reporting; Research Personnel; Resolution; Resources; Reverse Transcriptase Polymerase Chain Reaction; Role; Sampling; Site; Supervision; System; Testing; Time; Tissues; Transcript; Variant; base; biomarker identification; chromosome fusion; comparative; density; differential expression; disorder subtype; effective therapy; fusion gene; genome-wide; human data; human disease; innovation; interest; molecular subtypes; mortality; next generation; novel; oncology; osteosarcoma; preclinical study; prognostic assays; public health relevance; response biomarker; sarcoma; targeted treatment; transcriptome; transcriptome sequencing; transcriptomics; tumor; tumor progression; tumorigenesis

 DESCRIPTION (provided by applicant): Angiosarcomas are rare, highly aggressive cancers that originate from blood vessel-forming cells. Our understanding of the pathology of angiosarcomas is rudimentary; these tumors are diagnosed infrequently (fewer than 200 cases in the US each year) and they display extensive heterogeneity. This has made the development of effective therapies challenging. More than half of the patients with this disease die within the first year of diagnosis and tumor related mortality is extremely high. It is evident that a differet paradigm is needed to address the pathology and to develop effective treatments for this disease. The Opportunity: Hemangiosarcomas occur spontaneously and commonly in dogs (tens of thousands of cases in the US each year). Human angiosarcoma and canine hemangiosarcoma are morphologically and clinically indistinguishable. Molecular drivers of cancer progression are highly conserved among mammals. Specifically, we have documented the presence of orthologous non-random, recurrent chromosomal abnormalities in various tumors of humans and dogs that share anatomical and morphological features and that have comparable natural histories. This evolutionary conservation is not restricted to chromosomal aberrations; rather, it is apparent at the level of gene and microRNA expression. This provides a fundamental opportunity to reverse direction in comparative oncology and use canine tumors as a discovery system to identify potential, causative or pathognomonic events for homologous human diseases. We showed recently that canine hemangiosarcomas could be categorized into three molecular subtypes based on cell-autonomous properties and on their interactions with the microenvironment. Despite their complex, chaotic karyotypes, we identified a spectrum of recurrent inter-chromosomal fusion events (translocations) using next generation RNA sequencing. These were significantly associated with the different molecular subtypes, allowing us to consider development of specific targeted therapies to attack this disease. The plan: We will perform high-resolution RNA sequencing of idiopathic human angiosarcoma and non- malignant control tissues. The hypotheses are that the tumors will segregate into molecular subtypes that will be homologous to those we described for canine hemangiosarcoma, and that each subtype will be associated with translocations that will be orthologous to those found in the canine disease. We have selected to support this study through the R03 (discovery) mechanism as a means to provide proof-of-concept for additional studies as well as to develop a valuable resource for the scientific community working on sarcoma biology (RNA sequencing data for angiosarcomas does not exist in the public domain). The results from this project will enable us to embark on innovative, mechanistic projects to enhance our understanding of, and our capacity to manage this intractable disease.

 描述（由申请人提供）：血管肉瘤是一种罕见的、高度侵袭性的癌症，起源于血管形成细胞。我们对血管肉瘤病理学的了解还很初级。这些肿瘤很少被诊断出来（美国每年不到 200 例），并且它们表现出广泛的异质性。这使得有效疗法的开发具有挑战性。超过一半的患有这种疾病的患者会在短时间内死亡 诊断第一年与肿瘤相关的死亡率极高。显然，需要不同的范例来解决病理学问题并开发针对这种疾病的有效治疗方法。机会：血管肉瘤在狗中常见且自发发生（美国每年有数万例）。人类血管肉瘤和犬血管肉瘤在形态学和临床上无法区分。癌症进展的分子驱动因素在哺乳动物中高度保守。具体来说，我们已经记录了人类和狗的各种肿瘤中存在同源非随机、复发性染色体异常，这些肿瘤具有相同的解剖学和形态学特征，并且具有可比的自然史。这种进化保守性不仅限于染色体畸变。相反，它在基因和 microRNA 表达水平上很明显。这为扭转比较肿瘤学的方向并使用犬肿瘤作为发现系统来识别同源人类疾病的潜在、致病或病理事件提供了一个基本机会。我们最近表明，根据细胞自主特性及其与微环境的相互作用，犬血管肉瘤可以分为三种分子亚型。尽管其核型复杂、混乱，但我们使用下一代 RNA 测序鉴定了一系列反复发生的染色体间融合事件（易位）。这些与不同的分子亚型显着相关，使我们能够考虑开发特定的靶向疗法来攻击这种疾病。计划：我们将对特发性人类血管肉瘤和非恶性对照组织进行高分辨率 RNA 测序。假设肿瘤将分为与我们描述的犬血管肉瘤同源的分子亚型，并且每种亚型将与与犬疾病中发现的易位同源的易位相关。我们选择通过 R03（发现）机制支持这项研究，作为为其他研究提供概念验证的一种手段，并为从事肉瘤生物学研究的科学界开发宝贵的资源（公共领域不存在血管肉瘤的 RNA 测序数据）。该项目的结果将使我们能够开展创新的机械项目，以增强我们对这一棘手疾病的理解和管理能力。