Discovery and Pathogenetic Significance of Chromosome Translocations in Angiosarcom

 描述（由申请人提供）：血管瘤是一种罕见的高度侵袭性癌症，起源于血管形成细胞。我们对血管瘤的病理学的理解是初步的;这些肿瘤很少被诊断出来（在美国每年不到200例），并且它们表现出广泛的异质性。这使得开发有效的治疗方法具有挑战性。超过一半的患有这种疾病的患者在 第一年的诊断和肿瘤相关的死亡率非常高。很明显，需要一种新的范式来解决病理学问题，并开发有效的治疗方法。机会：血管瘤是自发性的，通常发生在狗身上（美国每年有数万例）。人血管肉瘤和犬血管肉瘤在形态学和临床上难以区分。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的正向非随机的、复发性的染色体异常，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。这种进化保守性并不局限于染色体畸变;相反，它在基因和microRNA表达水平上很明显。这提供了一个基本的机会，以扭转比较肿瘤学的方向，并使用犬肿瘤作为一个发现系统，以确定潜在的，致病性或特异性事件的同源人类疾病。我们最近发现，犬血管瘤可以分为三个分子亚型的基础上，细胞自主的特性和它们与微环境的相互作用。尽管它们的核型复杂、混乱，但我们使用下一代RNA测序鉴定了一系列复发性染色体间融合事件（易位）。这些与不同的分子亚型显著相关，使我们能够考虑开发特异性靶向治疗来治疗这种疾病。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。假设肿瘤将分离成与我们描述的犬血管肉瘤同源的分子亚型，并且每个亚型将与犬疾病中发现的易位相关。我们选择通过R 03（发现）机制支持这项研究，作为为其他研究提供概念验证的手段，并为从事肉瘤生物学研究的科学界开发有价值的资源（血管瘤的RNA测序数据不存在于公共领域）。该项目的结果将使我们能够着手开展创新的机械项目，以提高我们对这一棘手疾病的理解和管理能力。

 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.