Genetic profiles of different subsets of Merkel. cell carcinoma show links between combined and pure MCPyV-negative tumors
Genetic profiles of different subsets of Merkel. cell carcinoma show links between combined and pure MCPyV-negative tumors
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DOI：
10.1016/j.humpath.2017.10.014
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发表时间：
2018-01-01
期刊：
影响因子：
3.3
通讯作者：
Walsh, Noreen M.
中科院分区：
文献类型：
--
作者：
Carter, Michael D.;Gaston, Dan;Walsh, Noreen M.
默克尔细胞癌(MCC)的发生是由(1)默克尔细胞多瘤病毒(MCPyV)在肿瘤细胞中的克隆性整合和/或(2)紫外线的遗传损伤所驱动的。较高的突变负担、紫外线突变特征以及TP53和RBI基因的许多突变是病毒阴性亚群的特征。MCPyV阴性的MCC包括混合性(通常是鳞状和神经内分泌)和单纯(神经内分泌)肿瘤。由于合并的形态可能在显微镜下无法检测到，我们寻找了合并和纯病毒阴性肿瘤之间的遗传联系。采用全基因组微阵列技术对46例MCPyV阳性、9例MCPyV阴性和10例MCPyV联合阴性MCC进行了研究，以寻找拷贝数异常。通过下一代测序对整个队列(n=46)进行评估，以确定选定的肿瘤抑制基因和癌基因的突变。与MCPyV阳性病例相比，联合和单纯MCPyV阴性肿瘤的拷贝数异常更多，基因组的比例也更大(P<；在所有比较中均为0.01)。在两组MCPyV阴性组之间，这些参数均无差异。在MCPyV阴性的联合(8/10，80%)和单纯(7/9，78%)MCPyV阴性的肿瘤中，RBI拷贝数丢失或RBI失活突变(其中之一或两者)是常见的，但不是MCPyV阳性(1/9，11%)。在TP53中也出现了类似的趋势(合并[2/10，20%]和单纯病毒阴性肿瘤[5/9，56%]与单纯病毒阳性病例[0/9，0%]相比，显示基因拷贝数丢失或突变)。联合和纯MCPyV阴性肿瘤的共同基因图谱将这些亚群联系在一起，并将它们与MCPyV阳性肿瘤分开。(C)2017 Elsevier Inc.保留所有权利。
Tumorigenesis in Merkel cell carcinoma (MCC) is driven by (1) clonal integration of the Merkel cell polyomavirus (MCPyV) in neoplastic cells and/or (2) genetic damage by ultraviolet (UV) light. A higher mutational burden, a UV-mutational signature, and many mutations in the TP53 and RBI genes characterize the virus-negative subset. MCPyV-negative MCCs include combined (often squamous and neuroendocrine) and pure (neuroendocrine) tumors. Because a combined morphology could elude detection microscopically, we sought a genetic link between combined and pure virus-negative tumors. From a global cohort of 46 cases, 9 pure MCPyV-positive, 9 pure MCPyV-negative, and 10 combined MCPyV-negative MCCs were studied by genome-wide microarray in search of copy number aberrations. The entire cohort (n = 46) was evaluated by next-generation sequencing for mutations in selected tumor suppressor genes and oncogenes. More copy number aberrations and a greater fraction of the genome were changed in combined and pure MCPyV-negative tumors relative to MCPyV-positive cases (P < .01 for all comparisons). No difference in these parameters was found between the 2 MCPyV-negative groups. Copy number loss of RBI or an inactivating RBI mutation (either or both) was common in combined (8/10, 80%) and pure (7/9, 78%) MCPyV-negative tumors but not MCPyV-positive cases (1/9, 11%). A similar trend was seen for TP53 (combined [2/10, 20%] and pure virus-negative tumors [5/9, 56%] showed gene copy number loss or mutations contrasted with pure virus-positive cases [0/9, 0%]). The shared genetic profiles of combined and pure MCPyV-negative tumors link these subsets and separate them from MCPyV-positive tumors. (C) 2017 Elsevier Inc. All rights reserved.