Pathogenetics of Merkel cell cancer: a disease linked to UV damage & a new virus

描述(申请人提供)：默克尔细胞癌(MCC)是一种致命的神经内分泌皮肤癌，与环境紫外线暴露密切相关。在美国，每年有1500人被诊断为MCC，其疾病特异性死亡率是恶性黑色素瘤的两倍。有趣的是，大约15%的MCC与慢性日光损伤无关，这些MCC病例发生在较年轻的患者群体中。根据黑色素瘤的已知情况，对这些不同病因的MCC进行比较研究可能是有意义的。最近，在MCC肿瘤中发现了一种新的病毒(Merkel细胞多瘤病毒，MCPyV)。根据与动物致癌病毒的同源性，MCPyV可能导致一些MCC。然而，20%的MCC没有检测到MCPyV。在目标1中，我们将测试我们收集的150个广泛注释的MCC肿瘤的MCPyV。我们将比较MCPyV+和-肿瘤的临床结果，并探讨MCPyV和紫外线的关系。MCPyV有可能替代紫外线诱导的突变事件，因此我们推测，受阳光保护的MCC更有可能是病毒+。对MCC的定向研究尚未确定潜在的致病因素。我们已经进行了一次无偏见的全基因组筛查，并确定了几个在MCC中可能起癌基因作用的基因。为了确认和提炼这个列表，在目标2中，我们将对另外50个MCC肿瘤进行基于阵列的DNA和表达分析。这将是迄今为止规模最大的MCC遗传学研究，我们将进一步挖掘这一数据集，以检查MCPyV阳性和阴性肿瘤之间的差异。在目标3中，我们将通过经典的细胞培养生长、侵袭和转化实验来测试两个或更多可能的MCC癌基因的功能。至少将测试一种病毒基因和一种细胞基因。我们提出的研究可能会为针对这种鲜为人知的致命皮肤癌的治疗方法的未来发展提供关键的致病信息。该项目直接将临床与基础生物学联系起来，非常适合培养申请者成为内科科学家。公共卫生相关性：默克尔细胞癌(MCC)是一种非常致命的皮肤癌，与阳光照射和一种新发现的病毒有关。转移性MCC没有很好的治疗方法，在美国，MCC每年导致500人死亡。导致默克尔细胞癌的基因变化并不为人所知。更多地了解MCC出了什么问题，将使我们更好地了解阳光暴露是如何导致MCC的，以及我们未来可能如何设计有针对性的治疗方法。

DESCRIPTION (provided by applicant): Merkel cell carcinoma (MCC) is a deadly neuroendocrine skin cancer that is strongly associated with environmental UV exposure. MCC is diagnosed in 1500 persons each year in the United States and has twice the disease-specific mortality of malignant melanoma. Interestingly, about 15% of MCCs are not associated with chronic sun damage, and these MCC cases occur in a younger patient population. Based on what is known from melanoma, comparative study of these MCCs of different etiology is likely to be informative. Recently, a new virus (Merkel cell polyomavirus, MCPyV) was described in MCC tumors. Based on homology to viruses that cause cancer in animals, MCPyV probably contributes to some MCC. However, 20% of MCCs do not have detectable MCPyV. In Aim 1 we will test our collection of 150 extensively annotated MCC tumors for MCPyV. We will compare clinical outcomes of MCPyV + and - tumors and investigate the relationship between MCPyV and UV. It is possible that MCPyV may substitute for mutational events induced by UV, so we hypothesize that sun-protected MCCs are more likely to be virus +. Directed studies into MCC have not identified the underlying pathogenetics. We have performed an unbiased, genome-wide screen and identified several genes potentially acting as oncogenes in MCC. To confirm and refine this list, in Aim 2 we will perform array based DNA and expression analysis on 50 more MCC tumors. This will be the largest study of MCC genetics to date, and we will further mine this data set to examine differences between MCPyV positive and negative tumors. In Aim 3 we will test the functional capabilities of 2 or more putative MCC oncogenes by classic cell culture assays of growth, invasion, and transformation. At least 1 viral and 1 cellular gene will be tested. Our proposed studies are likely to provide key pathogenetic information required for the future development of therapies targeted to this poorly understood, lethal skin cancer. This project directly links the clinic with basic biology and is well suited for training the applicant for a career as a physician scientist. PUBLIC HEALTH RELEVANCE: Merkel cell carcinoma (MCC) is a very lethal skin cancer associated with sun exposure and a newly discovered virus. There are no good treatments for metastatic MCC and MCC kills 500 people a year in the United States. The genetic changes that cause Merkel cell cancer are not well known. Learning more about what goes wrong in MCC will give us a better understanding of how sun exposure causes MCC and how we might design targeted treatments in the future.