Discovery and Pathogenetic Significance of Chromosome Translocations in Angiosarcom

 描述(申请人提供)：血管肉瘤是一种罕见的高度侵袭性癌症，起源于血管形成细胞。我们对血管肉瘤的病理认识是初步的；这些肿瘤很少被诊断出来(美国每年不到200例)，而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 确诊的第一年，与肿瘤相关的死亡率极高。显然，需要一种不同的范式来解决这种疾病的病理问题和开发有效的治疗方法。机会：血管肉瘤是自发性的，通常发生在狗身上(美国每年有数万例)。人类血管肉瘤和犬血管肉瘤在形态和临床上是难以区分的。癌症进展的分子驱动因素在哺乳动物中高度保守。具体地说，我们记录了在人类和狗的各种肿瘤中存在同源的非随机的、重复的染色体异常，这些肿瘤具有相同的解剖和形态特征，并且具有类似的自然病史。这种进化保守并不局限于染色体异常；相反，它在基因和microRNA表达水平上是明显的。这为逆转比较肿瘤学的方向提供了一个基本的机会，并将犬类肿瘤作为一个发现系统来识别同源人类疾病的潜在、致病或致病事件。我们最近发现，犬血管肉瘤可以根据细胞自主特性和它们与微环境的相互作用分为三种分子亚型。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著相关，使我们能够考虑开发特定的靶向治疗来攻击这种疾病。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。假设肿瘤将分离成分子亚型，这些亚型将与我们描述的犬血管肉瘤同源，并且每个亚型都与与犬病中发现的易位相关。我们选择通过R03(发现)机制支持这项研究，作为一种手段，为其他研究提供概念验证，并为从事肉瘤生物学工作的科学界开发有价值的资源(血管肉瘤的RNA测序数据不存在于公共领域)。这个项目的结果将使我们能够着手进行创新的机械项目，以增强我们对这一顽固疾病的了解和管理能力。

 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.