Genomic evidence suggests that cutaneous neuroendocrine carcinomas can arise from squamous dysplastic precursors.
Genomic evidence suggests that cutaneous neuroendocrine carcinomas can arise from squamous dysplastic precursors.
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DOI：
10.1038/s41379-021-00928-1
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发表时间：
2022-04
期刊：
影响因子：
--
通讯作者：
Dlugosz AA
中科院分区：
文献类型：
--
作者：
Harms PW;Verhaegen ME;Hu K;Hrycaj SM;Chan MP;Liu CJ;Grachtchouk M;Patel RM;Udager AM;Dlugosz AA
默克尔细胞癌（MCC）是一种侵袭性皮肤神经内分泌癌，没有已知的发育异常前体。在某些情况下，MCC与上覆表皮中的SCCIS相关;然而，MCC和SCCIS群体显示出显著不同的形态，迄今为止尚未证明这些组分之间的关系。为了更好地理解这些不同肿瘤细胞群之间的关系，我们通过癌症分析面板评估了7对MCC-SCCIS的重叠基因组改变。一个子集的进一步特点是转录谱和免疫组化。在7个MCC-SCCIS对中的6个中，存在高度显著的突变重叠，包括共享的TP 53和/或RB 1突变。在某些情况下，在两种组分中均检测到先前与MCC相关的致癌事件（MYCL增加、MDM 4增加、HRAS突变）。虽然FBXW 7突变在MCC中富集，但在所有病例中，MCC组分没有独特的基因突变。转录组分析确定了MCC和SCCIS之间的2，736个差异表达基因。MCC组分中上调的基因包括Polycomb抑制复合物靶点;下调的转录物包括表皮标志物和免疫基因，如HLA-A。免疫组织化学研究显示MCC组分中SOX 2表达增加，H3 K27 Me 3、Rb和HLA-A表达减少。总之，MCC-SCCIS对证明了克隆相关性。向神经内分泌表型的转变与Rb蛋白表达的丧失、整体H3 K27 Me 3的减少和默克尔细胞基因如SOX 2的表达增加相关。我们的研究结果表明，在这种情况下，MCC的表皮起源，并据我们所知，提供了第一个分子证据，上皮内鳞状不典型增生可能是小细胞癌的直接前兆。
Merkel cell carcinoma (MCC) is an aggressive cutaneous neuroendocrine carcinoma without a known dysplastic precursor. In some cases, MCC is associated with SCCIS in the overlying epidermis; however, the MCC and SCCIS populations display strikingly different morphologies, and thus far a relationship between these components has not been demonstrated. To better understand the relationship between these distinct tumor cell populations, we evaluated 7 pairs of MCC-SCCIS for overlapping genomic alterations by cancer profiling panel. A subset was further characterized by transcriptional profiling and immunohistochemistry. In 6 of 7 MCC-SCCIS pairs there was highly significant mutational overlap including shared TP53 and/or RB1 mutations. In some cases, oncogenic events previously implicated in MCC (MYCL gain, MDM4 gain, HRAS mutation) were detected in both components. Although FBXW7 mutations were enriched in MCC, no gene mutation was unique to the MCC component across all cases. Transcriptome analysis identified 2,736 differentially expressed genes between MCC and SCCIS. Genes upregulated in the MCC component included Polycomb repressive complex targets; downregulated transcripts included epidermal markers, and immune genes such as HLA-A. Immunohistochemical studies revealed increased expression of SOX2 in the MCC component, with diminished H3K27Me3, Rb, and HLA-A expression. In summary, MCC-SCCIS pairs demonstrate clonal relatedness. The shift to neuroendocrine phenotype is associated with loss of Rb protein expression, decrease in global H3K27Me3, and increased expression of Merkel cell genes such as SOX2. Our findings suggest an epidermal origin of MCC in this setting, and to our knowledge provide the first molecular evidence that intraepithelial squamous dysplasia may represent a direct precursor for small cell carcinoma.
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影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
影响因子：
16.6
作者：
Aran D;Camarda R;Odegaard J;Paik H;Oskotsky B;Krings G;Goga A;Sirota M;Butte AJ
通讯作者：
Butte AJ
影响因子：
30.3
作者：
Kwun HJ;Shuda M;Feng H;Camacho CJ;Moore PS;Chang Y
通讯作者：
Chang Y
影响因子：
6.5
作者：
Kervarrec, Thibault;Aljundi, Mohanad;Houben, Roland
通讯作者：
Houben, Roland
DOI：
10.1038/modpathol.2017.8
发表时间：
2017-06
期刊：
Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc
影响因子：
--
作者：
Busam KJ;Pulitzer MP;Coit DC;Arcila M;Leng D;Jungbluth AA;Wiesner T
通讯作者：
Wiesner T