Department of Pathology and Laboratory Medicine, QEII Health Sciences Centre, Nova Scotia Health (Central Zone), Halifax, NS, Canada.
Department of Pathology, Dalhousie University, Halifax, NS, Canada.
Mod Pathol. 2022 Dec;35(12):1829-1836. doi: 10.1038/s41379-022-01151-2. Epub 2022 Sep 8.
Merkel cell carcinoma (MCC) is an aggressive cutaneous neuroendocrine (NE) carcinoma arising from integration of Merkel cell polyomavirus (MCPyV) DNA into a host cell or from ultraviolet light-induced genetic damage (proportions vary geographically). Tumors in the latter group include those with "pure" NE phenotype and those "combined" with other elements, most often squamous cell carcinoma (SCC). We performed comprehensive genomic profiling (CGP) of MCPyV+ and MCPyV- (pure and combined) tumors, to better understand their mutational profiles and shed light on their pathogenesis. Supplemental immunohistochemistry for Rb expression was also undertaken. After eliminating low quality samples, 37 tumors were successfully analyzed (14 MCPyV+, 8 pure MCPyV- and 15 combined MCPyV-). The SCC and NE components were sequenced separately in 5 combined tumors. Tumor mutational burden was lower in MCPyV+ tumors (mean 1.66 vs. 29.9/Mb, P < 0.0001). MCPyV- tumors featured frequent mutations in TP53 (95.6%), RB1 (87%), and NOTCH family genes (95.6%). No recurrently mutated genes were identified in MCPyV+ tumors. Mutational overlap in the NE and SCC components of combined tumors was substantial ('similarity index' >24% in 4/5 cases). Loss of Rb expression correlated with RB1 mutational (P < 0.0001) and MCPyV- status (P < 0.0001) in MCCs and it was observed more frequently in the SCC component of combined MCC than in a control group of conventional cutaneous SCC (P = 0.0002). Our results (i) support existing evidence that MCPyV+ and MCPyV- MCCs are pathogenetically distinct entities (ii) concur with earlier studies linking the NE and SCC components of combined MCCs via shared genetic profiles and (iii) lend credence to the proposal that an Rb-deficient subset of SCC's is the source of phenotypically divergent combined MCCs.
默克尔细胞癌（Merkel cell carcinoma，MCC）是一种侵袭性皮肤神经内分泌（neuroendocrine，NE）癌，由 Merkel 细胞多瘤病毒（Merkel cell polyomavirus，MCPyV）DNA 整合入宿主细胞或由紫外线诱导的遗传损伤引起（其比例在不同地区有所差异）。后者群体中的肿瘤包括具有“纯”NE 表型的肿瘤和那些“混合”有其他成分的肿瘤，最常见的是鳞状细胞癌（squamous cell carcinoma，SCC）。我们对 MCPyV+和 MCPyV-（纯和混合）肿瘤进行了全面的基因组分析（genomic profiling，CGP），以更好地了解它们的突变特征，并阐明它们的发病机制。还进行了 Rb 表达的补充免疫组织化学检测。在消除低质量样本后，成功分析了 37 个肿瘤（14 个 MCPyV+，8 个纯 MCPyV-和 15 个混合 MCPyV-）。在 5 个混合肿瘤中，分别对 SCC 和 NE 成分进行了测序。MCPyV+肿瘤的肿瘤突变负担较低（平均 1.66 与 29.9/Mb，P < 0.0001）。MCPyV-肿瘤中频繁出现 TP53（95.6%）、RB1（87%）和 NOTCH 家族基因（95.6%）的突变。在 MCPyV+肿瘤中未鉴定出经常发生突变的基因。在混合肿瘤的 NE 和 SCC 成分之间存在大量的突变重叠（在 4/5 例中“相似性指数”>24%）。在 MCC 中，Rb 表达缺失与 RB1 突变（P < 0.0001）和 MCPyV-状态（P < 0.0001）相关，在混合 MCC 的 SCC 成分中比在常规皮肤 SCC 的对照组中更常见（P = 0.0002）。我们的结果（i）支持现有的证据，即 MCPyV+和 MCPyV- MCC 是具有不同发病机制的实体；（ii）与早期研究一致，这些研究通过共享的遗传特征将混合 MCC 的 NE 和 SCC 成分联系起来；（iii）证明了 Rb 缺失的 SCC 亚组是表型不同的混合 MCC 的来源的假说。
