Reduced H3K27me3 expression in Merkel cell polyoma virus-positive tumors.
Reduced H3K27me3 expression in Merkel cell polyoma virus-positive tumors.
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DOI：
10.1038/modpathol.2017.8
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发表时间：
2017-06
期刊：
影响因子：
--
通讯作者：
Wiesner T
中科院分区：
文献类型：
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作者：
Busam KJ;Pulitzer MP;Coit DC;Arcila M;Leng D;Jungbluth AA;Wiesner T
默克尔细胞癌是一种原发性皮肤神经内分泌癌，一旦转移是很难治疗的。最近的突变分析默克尔细胞癌揭示了低数量的突变在默克尔细胞多瘤病毒相关的肿瘤，和大量的突变在病毒阴性的鳞状细胞癌和神经内分泌癌的慢性阳光损伤的皮肤。我们推测，病毒阳性默克尔细胞癌中突变的缺乏可能反映了一种病理机制，即依赖于染色质的紊乱而不改变DNA序列（表观遗传失调）。一个中心的表观遗传调节因子是Polycomb抑制复合物2（PRC2），其通过使组蛋白H3的赖氨酸（K）27三甲基化而使基因组区域沉默，从而建立组蛋白标记H3K27me3。最近的实验研究数据表明，小鼠皮肤中PRC2的缺失导致默克尔细胞的形成。根据这些发现，我们探索了PRC2缺失在人类默克尔细胞癌中的可能作用。我们检测了35例具有单纯组织学特征的默克尔细胞癌（22例原发性和13例转移性病变）和5例皮肤鳞状细胞癌和神经内分泌癌中H3 K27 me3的免疫组化表达。我们发现在具有纯组织学特征的肿瘤和病毒阳性的默克尔细胞癌中H3K27 me3染色强烈减少。联合神经内分泌癌没有或只有最小的损失H3K27me3标记。我们的研究结果表明，PRC2介导的表观遗传失调可能在病毒阳性默克尔细胞癌和具有纯组织学特征的肿瘤的发病机制中发挥作用。
Merkel cell carcinoma is a primary cutaneous neuroendocrine carcinoma, which once metastatic is difficult to treat. Recent mutation analyses of Merkel cell carcinoma revealed a low number of mutations in Merkel cell polyomavirus-associated tumors, and a high number of mutations in virus-negative combined squamous cell and neuroendocrine carcinomas of chronically sun-damaged skin. We speculated that the paucity of mutations in virus-positive Merkel cell carcinoma may reflect a pathomechanism that depends on derangements of chromatin without alterations in the DNA sequence (epigenetic dysregulation). One central epigenetic regulator is the Polycomb repressive complex 2 (PRC2), which silences genomic regions by trimethylating (me3) lysine (K) 27 of histone H3, and thereby establishes the histone mark H3K27me3. Recent experimental research data demonstrated that PRC2 loss in mice skin results in the formation of Merkel cells. Prompted by these findings, we explored a possible contribution of PRC2 loss in human Merkel cell carcinoma. We examined the immunohistochemical expression of H3K27me3 in 35 Merkel cell carcinomas with pure histological features (22 primary and 13 metastatic lesions) and in 5 combined squamous and neuroendocrine carcinomas of the skin. We found a strong reduction of H3K27me3 staining in tumors with pure histologic features and virus-positive Merkel cell carcinomas. Combined neuroendocrine carcinomas had no or only minimal loss of H3K27me3 labeling. Our findings suggest that a PRC2-mediated epigenetic deregulation may play a role in the pathogenesis of virus-positive Merkel cell carcinomas and in tumors with pure histologic features.