Cervical cancer can arise from cells containing exclusively episomes, and for HPV16, around 30% (26–76% depending on study) of cervical cancers develop in this way [54], [180] and [181]. Around 70% of HPV16-associated cervical cancers contain integrated HPV16 sequences, while for HPV18, the viral genome is almost exclusively integrated [182], SKI-606 supplier [183], [184], [185] and [186]. In both cases, however, it is the long-term expression, and in particular, the over-expression of E6 and E7 and the accumulation of genetic errors, which are ultimately important in the progression from CIN3 to cervical cancer. Although most research on HPVs
has focused on the high-risk types from the Alpha genus, it is apparent that the low-risk types can very occasionally be linked with cancer progression, such as in persistent RRP [187]. Several reports have suggested that duplications within the HPV genome or occasional
integration may be important in these cases [188] and [189], but given the different functions of the low-risk E6 and E7 proteins, we would not expect the mechanisms of how these viruses predispose to cancer to be the same as for the high-risk types. Even so, it does appear that persistence is an important indicator of cancer risk in both cases, prompting the search for better methods of disease Selleck SP600125 treatment for low-risk PV types. Clearly, the genetic susceptibility of the host can play an important role in some cancers associated with low-risk HPV types, as evidenced from the study of WHIMS
and EV [35] and [38], the latter of which is associated with Beta HPV types that are usually only associated with asymptomatic infection in the general population. In EV patients, Beta HPVs are clearly associated with the development of non-melanoma skin cancer (NMSC; the most common cancer in adult light-skinned populations [190]), but in the general population and in immunosuppressed individuals, this has been the subject of much debate [191], [192] and [193]. These discussions have been stimulated, to a large extent, by the failure to detect Beta HPV DNA ubiquitously in skin cancers (in contrast to the situation seen Adenosine for the high-risk Alpha PVs in cervical cancer), and the finding that HPVs from the Beta genus are prevalent in normal skin even in the absence of disease. It appears however that these viruses may stimulate cancer progression in a manner that is mechanistically different to HPVs from the high-risk Alpha group. Indeed, our current thinking suggests that the E6 and E7 proteins from these HPV types may exert their effects at an early stage in the carcinogenesis process by inhibiting normal DNA damage repair or apoptosis in response to sunlight [194], [195], [196] and [197].
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