Kervarrec Thibault, Appenzeller Silke, Samimi Mahtab, Sarma Bhavishya, Sarosi Eva-Maria, Berthon Patricia, Le Corre Yannick, Hainaut-Wierzbicka Ewa, Blom Astrid, Benethon Nathalie, Bens Guido, Nardin Charline, Aubin Francois, Dinulescu Monica, Jullie Marie-Laure, Pekár-Lukacs Ágnes, Calonje Eduardo, Thanguturi Soumanth, Tallet Anne, Wobser Marion, Touzé Antoine, Guyétant Serge, Houben Roland, Schrama David
Department of Pathology, University Hospital Center of Tours, University of Tours, Tours, France; Biologie des infections à polyomavirus team, UMR INRAE ISP 1282, University of Tours, Tours, France; Department of Dermatology, Venereology and Allergology, University Hospital Würzburg, Würzburg, Germany.
Core Unit Bioinformatics, Comprehensive Cancer Center Mainfranken, University Hospital Würzburg, Würzburg, Germany.
J Invest Dermatol. 2022 Mar;142(3 Pt A):516-527. doi: 10.1016/j.jid.2021.07.175. Epub 2021 Sep 1.
Although virus-negative Merkel cell carcinoma (MCC) is characterized by a high frequency of UV-induced mutations, the expression of two viral oncoproteins is regarded as a key mechanism driving Merkel cell polyomavirus‒positive MCC. The cells in which these molecular events initiate MCC oncogenesis have yet not been identified for both MCC subsets. A considerable proportion of virus-negative MCC is found in association with squamous cell carcinoma (SCC), suggesting (i) coincidental collision, (ii) one providing a niche for the other, or (iii) one evolving from the other. Whole-exome sequencing of four combined tumors consisting of SCC in situ and Merkel cell polyomavirus‒negative MCC showed many mutations shared between SCC and MCC in all cases, indicating a common ancestry and thereby a keratinocytic origin of these MCCs. Moreover, analyses of the combined cases as well as of pure SCC and MCC suggest that RB1 inactivation in SCC facilitates MCC development and that epigenetic changes may contribute to the SCC/MCC transition.
尽管病毒阴性的默克尔细胞癌（MCC）具有紫外线诱导突变频率高的特点，但两种病毒癌蛋白的表达被认为是驱动默克尔细胞多瘤病毒阳性MCC的关键机制。对于这两种MCC亚型，尚未确定这些分子事件引发MCC肿瘤发生的细胞。相当一部分病毒阴性MCC与鳞状细胞癌（SCC）相关，提示（i）巧合碰撞，（ii）一方为另一方提供微环境，或（iii）一方由另一方演变而来。对4例由原位SCC和默克尔细胞多瘤病毒阴性MCC组成的联合肿瘤进行全外显子测序显示，在所有病例中，SCC和MCC之间存在许多共同突变，表明这些MCC有共同的起源，因此其起源于角质形成细胞。此外，对联合病例以及单纯SCC和MCC的分析表明，SCC中RB1失活促进MCC发展，表观遗传变化可能有助于SCC/MCC转变。
