Harms Kelly L, Lazo de la Vega Lorena, Hovelson Daniel H, Rahrig Samantha, Cani Andi K, Liu Chia-Jen, Fullen Douglas R, Wang Min, Andea Aleodor A, Bichakjian Christopher K, Johnson Timothy M, Tomlins Scott A, Harms Paul W
Department of Dermatology, University of Michigan Medical School, Ann Arbor2Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor.
Michigan Center for Translational Pathology, University of Michigan, Ann Arbor4Department of Pathology, University of Michigan Medical School, Ann Arbor.
JAMA Dermatol. 2017 Jun 1;153(6):505-512. doi: 10.1001/jamadermatol.2017.0507.
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.
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 cases met 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.
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.
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.
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.
默克尔细胞癌（MCC）是一种侵袭性皮肤神经内分泌癌。在罕见情况下，额外的皮肤MCC肿瘤的发生在临床上符合第二原发性MCC肿瘤而非皮肤转移，这具有重要的治疗和预后意义。
评估4例临床诊断为多发性原发性MCC患者的基因相关性。
设计、背景和参与者：在这个病例系列中，识别出7例临床诊断为多发性原发性MCC的病例；4例符合下一代测序（NGS）分析的纳入标准。对临床诊断的多发性原发性肿瘤之间的突变、拷贝数改变和默克尔细胞多瘤病毒（MCPyV）序列进行分析和比较，以表征基因相关性，从而评估克隆性。临床诊断为多发性原发性MCC的患者是从密歇根大学的多学科MCC项目（一个三级护理中心）中识别出来的。
通过肿瘤测序和靶向MCPyV测序对4例临床诊断为多发性原发性MCC的病例进行表征，以区分独立的原发性肿瘤和相关转移瘤。
总体而言，纳入并分析了4例年龄在70多岁或80多岁的患者。病例1和病例4被确认为基因上不同的原发性肿瘤，没有相似的拷贝数改变，也没有显著的突变重叠。病例2和病例3基于重叠的拷贝数改变被认定为克隆相关。在克隆相关的肿瘤中，染色体拷贝数变化比突变更可靠地证明克隆性。无论克隆性如何，我们发现所有肿瘤对的MCPyV状态都是一致的，并且MCPyV阳性肿瘤主要含有亚克隆突变。
我们的研究结果表明，MCC患者可能会发生第二个基因上不同的原发性肿瘤；在这种情况下，后续肿瘤可能通过类似的发病机制发展，无论是MCPyV介导的还是紫外线介导的。对染色体拷贝数变化和突变进行下一代测序分析有助于区分多发性原发性MCC与临床上类似多发性原发性病变的MCC进展，从而为患者进行适当的分期。
