Molecular Profiling of Multiple Primary Merkel Cell Carcinoma to Distinguish Genetically Distinct Tumors From Clonally Related Metastases
Molecular Profiling of Multiple Primary Merkel Cell Carcinoma to Distinguish Genetically Distinct Tumors From Clonally Related Metastases
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DOI：
10.1001/jamadermatol.2017.0507
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发表时间：
2017-06-01
期刊：
影响因子：
10.9
通讯作者：
Harms, Paul W.
中科院分区：
文献类型：
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作者：
Harms, Kelly L.;de la Vega, Lorena Lazo;Harms, Paul W.
重要性默克尔细胞癌(MCC)是一种侵袭性皮肤神经内分泌癌。目的评估4例临床诊断为多原发MCC的患者的遗传关联性。设计、背景和研究对象：本研究共鉴定了7例临床指定的多原发MCC；4例符合下一代测序(NGS)分析的纳入标准。分析和比较临床指定的多原发瘤之间的突变、拷贝数改变和默克尔细胞多瘤病毒(MCPyV)序列，以确定遗传相关性，从而评估克隆性。临床指定的多原发MCC患者来自于密歇根大学的多学科MCC项目，该中心是一个三级护理中心。主要结果和测量4例临床指定的多原发微细胞癌患者通过肿瘤测序和靶向MCPyV测序来区分独立的原发肿瘤和相关的转移。例1和4被证实为遗传上不同的原发肿瘤，没有相似的拷贝数变化或显示显著的突变重叠。根据重叠的拷贝数改变，病例2和3被指定为克隆性相关。在克隆性相关肿瘤中，染色体拷贝数变化比突变更能可靠地显示克隆性。不考虑克隆性，我们发现MCPyV状态在所有肿瘤对中是一致的，并且MCPyV阳性肿瘤以亚克隆性突变为主。结论和相关性我们的研究结果提示MCC患者可能发生第二个基因上不同的原发肿瘤；在这种情况下，后续肿瘤可能通过类似的发病机制发展，要么是MCPyV介导的，要么是紫外线介导的。对染色体拷贝数变化和突变的下一代测序分析有助于区分多个原发MCC和临床上类似于多个原发MCC的进展，从而对患者进行适当的分期。
IMPORTANCE Merkel cell carcinoma (MCC) is an aggressive cutaneous neuroendocrine carcinoma. In rare cases, the development of an additional cutaneous MCC tumor is clinically consistent with a second primary MCC tumor rather than a cutaneous metastasis, which has important treatment and prognostic implications.OBJECTIVE To evaluate genetic relatedness in 4 cases with the clinical diagnosis of multiple primary MCCs.DESIGN, SETTING, AND PARTICIPANTS In this case series, 7 cases of clinically designated multiple primary MCC were identified; 4 casesmet inclusion criteria for next-generation sequencing (NGS) analysis. Mutations, copy number alterations, and Merkel cell polyomavirus (MCPyV) sequence were analyzed and compared between clinically designated multiple primary tumors to characterize genetic relatedness and hence assess clonality. Patients with clinically designated multiple primary MCC were identified from the multidisciplinary MCC Program at the University of Michigan, a tertiary care center.MAIN OUTCOMES AND MEASURES Four cases of clinically designated multiple primary MCC were characterized by tumor sequencing and targeted MCPyV sequencing to distinguish independent primary tumors from related metastases.RESULTS Overall, 4 patients in their 70s or 80s were included and analyzed. Cases 1 and 4 were verified as genetically distinct primary tumors and did not harbor similar copy number alterations or demonstrate significant mutational overlap. Cases 2 and 3 were designated as clonally related based on overlapping copy number alterations. In clonally related tumors, chromosomal copy number changes were more reliable than mutations for demonstrating clonality. Regardless of clonality, we found that MCPyV status was concordant for all tumor pairs and MCPyV positive tumors harbored predominatly subclonal mutations.CONCLUSIONS AND RELEVANCE Our findings suggest that patients with MCC may develop a second genetically distinct primary tumor; in this case, the subsequent tumor is likely to develop through similar mechanisms of pathogenesis, either MCPyV-mediated or ultraviolet light-mediated. Next-generation sequencing analysis of chromosomal copy number changes and mutations is useful in distinguishing multiple primary MCCs from progression of MCC clinically resembling multiple primaries, allowing appropriate staging of the patient.