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

It harbours a dsDNA virus of approximately 5.4kb, and encodes seven
viral proteins spanning two different genomic regions: (i) the early region,
encompassing the Large T antigen (LT), the small T antigen (ST), the 57kT
protein, and the alternative T open reading frame (ALTO); (ii) the late region,
essential for the capsid formation and viral replication, encoding the three
capsid proteins VP1, VP-2, and VP-3 (9).  MCV is of particular interest
as a model system for studying oncogenic mechanisms, due to the low number of
viral proteins, and its well-established role in oncogenesis. Besides its high
prevalence in MCCs, it has been shown that MCV is clonally integrated when
detected in such neoplasia, while it remains episomal in non-malignant cells.
In MCCs, integrated MCV constituvely expresses viral proteins that are
transiently expressed in non-cancer cells (8).
Also, MCV encodes seven proteins, including the Large T (LT; which is truncated
in all MCCs) and the small T (ST) antigens. Interestingly, downregulation of LT
or ST impairs MCV+ MCCs growth (10-12). LT
has been shown to be involved in MCC oncogenesis through its ability to
sequester RB, thus inhibiting RB-E2F1 binding and promoting E2F1 release,
consequently leading to cell cycle progression (10). This
binding appears as an essential oncogenic mechanisms associated with MCV (13). LT has been involved in other mechanisms, e.g. lysosomal pathway control (14) or
downregulation of Toll-like receptor 9 (TLR9) expression (15),
putatively participating in MCC pathogenesis. ST has been shown to bind and impair
the SCF/FBXW7 ubiquitin ligase function, thus leading to a defect of LT
ubiquitination and clearance (as well as cell cycle promoting substrates such
as cyclin E and Myc). It has also been recently reported that ST could impair
the microtubule network (16) and
the actin cytoskeleton (17), thus
potentially facilitating cell motility and migration.

An additional strong evidence of the driving role of MCV in MCCs comes
from 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 the
average of epithelial cancers), whereas the MCV- MCCs harbour a very high
mutation burden (~40 mutations/Mb) (18-20). The
genomes of MCV+ MCCs display an aging-related pattern, with no recurrent
alteration of known oncogenes or tumour suppressors, in contrast with the
UV-induced mutation pattern detected in MCV- MCCs. Indeed, the MCV- MCCs
harbour specific oncogenic mutations (such as inactivating mutation of RB), and
are more frequent in Australia, where sun-exposure of head and neck appears as
the main etiology (21).

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Overall, these are solid evidence of the oncogenic driving role of MCV
when present in MCCs, making it a powerful model for oncogenic systems-wide
study. Additional publications describe a sporadic association of MCV with
non-small cell lung carcinoma (22,
23),
notably through an impact on the microRNA profile in MCV+ NSCLC. Further
investigations remain to be conducted to directly link MCV to this neoplasia.