Batinica M, Akgül B, Silling S, Mauch C, Zigrino P
Department of Dermatology and Venereology, University of Cologne, Germany.
Institute of Virology, University of Cologne, Germany.
J Dermatol Sci. 2015 Jul;79(1):43-9. doi: 10.1016/j.jdermsci.2015.04.002. Epub 2015 Apr 14.
Merkel cell carcinoma (MCC) is a neuroendocrine cancer of the skin postulated to originate through Merkel cell polyomavirus (MCPyV) oncogenesis and/or by mutations in molecules implicated in the regulation of cell growth and survival. Despite the fact that MCPvV is detected more broadly within the population, only a part of the infected people also develop MCC. It is thus conceivable that together, virus and for example mutations, are necessary for disease development. However, apart from a correlation between MCPyV positivity or mutations and MCC development, less is known about the association of these factors with progressive disease.
To analyze MCPyV positivity, load and integration in MCC as well as presence of mutations in PDGFRα and TP53 genes and correlate these with clinical features and disease progression to identify features with prognostic value for clinical progression.
This is a study on a MCC population group of 64 patients. MCPyV positivity, load and integration in parallel to mutations in the PDGFRα and TP53 were analyzed on genomic DNA from MCC specimens. In addition, expression of PDGFRα, survivin and p53 proteins was analyzed by immunodetection in tissues specimens. All these parameters were analyzed as function of patient's disease progression status.
83% of MCCs were positive for the MCPyV and among these 36% also displayed virus-T integration. Viral load ranged from 0.006 to 943 viral DNA copies/β-globin gene and was highest in patients with progressive disease. We detected more than one mutation within the PDGFRα gene and identified two new SNPs in 36% of MCC patients, whereas no mutations were found in TP53 gene. Survivin was expressed in 78% of specimens. We could not correlate either mutations in PDGFR or expression of PDGFR, p53 and surviving either to the disease progression or to the MCPyV positivity.
In conclusion, our data indicate that the viral positivity when associated with high viral load, correlates with poor disease outcome. Frequent mutations in the PDGFRα gene and high survivin expression were found in MCC independent of the viral positivity. These data suggest that these three factors independently contribute to Merkel cell carcinoma development and that only the viral load can be used as indicator of disease progression in virus positive patients.
默克尔细胞癌（MCC）是一种皮肤神经内分泌癌，据推测其起源于默克尔细胞多瘤病毒（MCPyV）致癌作用和/或参与细胞生长与存活调控的分子发生突变。尽管在人群中更广泛地检测到MCPyV，但只有一部分感染者会患上MCC。因此可以想象，病毒以及例如突变等因素共同作用对于疾病发展是必要的。然而，除了MCPyV阳性或突变与MCC发展之间的关联外，对于这些因素与疾病进展的关联了解较少。
分析MCC中MCPyV的阳性率、载量和整合情况，以及血小板衍生生长因子受体α（PDGFRα）和TP53基因的突变情况，并将这些与临床特征和疾病进展相关联，以确定对临床进展具有预后价值的特征。
这是一项对64例MCC患者群体的研究。对MCC标本的基因组DNA分析MCPyV的阳性率、载量和整合情况，同时分析PDGFRα和TP53的突变情况。此外，通过免疫检测分析组织标本中PDGFRα、生存素和p53蛋白的表达。所有这些参数均作为患者疾病进展状态的函数进行分析。
83%的MCC为MCPyV阳性，其中36%还显示病毒-T整合。病毒载量范围为0.006至943个病毒DNA拷贝/β-珠蛋白基因，在疾病进展患者中最高。我们在PDGFRα基因中检测到不止一个突变，并在36%的MCC患者中鉴定出两个新的单核苷酸多态性（SNP），而在TP53基因中未发现突变。78%的标本中表达生存素。我们无法将PDGFR的突变或PDGFR、p53和生存素的表达与疾病进展或MCPyV阳性相关联。
总之，我们的数据表明，病毒阳性与高病毒载量相关时，与疾病不良预后相关。在MCC中发现PDGFRα基因频繁突变和生存素高表达，与病毒阳性无关。这些数据表明这三个因素独立促成默克尔细胞癌的发生，并且只有病毒载量可作为病毒阳性患者疾病进展的指标。
