It the UV-induced mutation pattern detected in MCV- MCCs.

It harbours a dsDNA virus of approximately 5.4kb, and encodes sevenviral proteins spanning two different genomic regions: (i) the early region,encompassing the Large T antigen (LT), the small T antigen (ST), the 57kTprotein, and the alternative T open reading frame (ALTO); (ii) the late region,essential for the capsid formation and viral replication, encoding the threecapsid proteins VP1, VP-2, and VP-3 (9).  MCV is of particular interestas a model system for studying oncogenic mechanisms, due to the low number ofviral proteins, and its well-established role in oncogenesis. Besides its highprevalence in MCCs, it has been shown that MCV is clonally integrated whendetected in such neoplasia, while it remains episomal in non-malignant cells.In MCCs, integrated MCV constituvely expresses viral proteins that aretransiently expressed in non-cancer cells (8).

Also, MCV encodes seven proteins, including the Large T (LT; which is truncatedin all MCCs) and the small T (ST) antigens. Interestingly, downregulation of LTor ST impairs MCV+ MCCs growth (10-12). LThas been shown to be involved in MCC oncogenesis through its ability tosequester RB, thus inhibiting RB-E2F1 binding and promoting E2F1 release,consequently leading to cell cycle progression (10). Thisbinding appears as an essential oncogenic mechanisms associated with MCV (13). LT has been involved in other mechanisms, e.g. lysosomal pathway control (14) ordownregulation of Toll-like receptor 9 (TLR9) expression (15),putatively participating in MCC pathogenesis. ST has been shown to bind and impairthe SCF/FBXW7 ubiquitin ligase function, thus leading to a defect of LTubiquitination and clearance (as well as cell cycle promoting substrates suchas cyclin E and Myc).

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It has also been recently reported that ST could impairthe microtubule network (16) andthe actin cytoskeleton (17), thuspotentially facilitating cell motility and migration. An additional strong evidence of the driving role of MCV in MCCs comesfrom the comparison between the mutational burden of MCV+ and MCV- MCCs. MCV+MCCs shows a somatic mutation rate of 0.4-0.75 mutations/Mb (lower than theaverage of epithelial cancers), whereas the MCV- MCCs harbour a very highmutation burden (~40 mutations/Mb) (18-20). Thegenomes of MCV+ MCCs display an aging-related pattern, with no recurrentalteration of known oncogenes or tumour suppressors, in contrast with theUV-induced mutation pattern detected in MCV- MCCs.

Indeed, the MCV- MCCsharbour specific oncogenic mutations (such as inactivating mutation of RB), andare more frequent in Australia, where sun-exposure of head and neck appears asthe main etiology (21). Overall, these are solid evidence of the oncogenic driving role of MCVwhen present in MCCs, making it a powerful model for oncogenic systems-widestudy. Additional publications describe a sporadic association of MCV withnon-small cell lung carcinoma (22,23),notably through an impact on the microRNA profile in MCV+ NSCLC. Furtherinvestigations remain to be conducted to directly link MCV to this neoplasia.