The molecular genetics of NMSC has been widely studied in both BCC and SCC. In this context, the study of loss of heterozygosity (LOH) patterns has provided important insights into the genetic abnormalities underlying these tumour types. In relation to BCC, the study of the familial naevoid basal cell carcinoma (NBCC) syndrome by LOH analysis revealed consistent loss of chromosome arm 9q 121, 122. This region contains the tumour suppressor gene PTCH, which maps to 9q22–31, and is an important regulator of the sonic hedgehog-signalling pathway. Germline inactivation of PTCH is a common event in NBCC 123, 124 and LOH is commonly observed at 9q22 125–127. Mutations in PTCH can also be detected in sporadic forms of BCC 128. Therefore, PTCH and regulation of the sonic hedgehog pathway play an important role in BCC development, and studies are ongoing into its use as a therapeutic target (reviewed in ref 129). PTCH mutations can be found in SCCs from patients with a history of multiple BCCs 130. However, the role of PTCH, if any, in SCC remains to be elucidated. The molecular genetics of SCC is less clear, however. LOH analysis of SCC tumours where the HPV status was not determined revealed widespread loss of markers from as many as 39 chromosomal arms, with frequent loss observed at 9p, 13q, 17p, 17q, and 3p 131. Therefore, unlike BCC, there is no distinct association between a specific genetic abnormality and predisposition to SCC. It is, however, likely that key genes are involved in the development of SCC, and they may or may not be associated with these regions of LOH. 9p21 loss, containing the p16INK4a and p14ARF tumour suppressor genes, has been shown to be a common event in SCC tumours. Furthermore, p16INK4a and p14ARF are commonly inactivated in SCC, by promoter hypermethylation 132. It is likely that these two genes are important in the development of SCC and that further genetic and epigenetic mechanisms play a role in SCC development. How p16INK4a and p14ARF are inactivated in HPV-positive cells, and whether different patterns of LOH are observed in HPV-positive and -negative cancers, may provide important clues to discovering tumour suppressor genes inactivated in NMSC.
Specific underlying genetic defects may predispose to HPV infection and disease. One example of this is the association between severe combined immune deficiency (SCID) in humans and predisposition to chronic HPV disease. SCID is caused by several known genetic defects 133 and many SCID sufferers have chronic HPV disease. Chronic HPV infections often develop late following corrective haemopoietic stem-cell transplantation and are limited to the skin, and in many cases present with lesions typical of EV patients. The EV HPV types 5, 14, and 36, and the wart-causing types 2, 3, and 57 are commonly isolated from SCID patients 134. The mechanism promoting HPV infection in SCID patients is linked to declining or insufficient immune function, but the model elegantly demonstrates the potential molecular events that may underlie HPV-associated NMSC development.