Susceptibility and modifier genes in cutaneous basal cell carcinomas and their associations with clinical phenotype

While ultraviolet radiation (UV) is critical in the pathogenesis of basal cell carcinomas (BCC), its role in determining the phenotypic variation shown by patients is unknown. Thus, patients manifest variation in BCC numbers, patterns of presentation and tumour site. We have used this diversity to classify patients into subgroups that are associated with different risks of developing tumours. Two phenotypes are particularly interesting. Firstly, presentation with clusters of BCC. These patients, termed multiple presentation phenotype (MPP), had two to five BCC at one presentation, suggesting rapid accrual over short periods of time. They comprised 15% of our 1200 BCC patients. A minority of patients demonstrated multiple clustering events, a phenomenon that is associated with a genetic pre-disposition. The second risk phenotype, characterised by tumours on the trunk, is also associated with a pre-disposition. Both phenotypes were characterised by a susceptibility to develop numerous BCC. Thus, all our patients with more than five BCC had one or both of these phenotypes. We are using a candidate gene approach to identify loci associated with risk of these phenotypes (susceptibility genes) and tumour numbers in them (modifier genes). Interestingly, we did not identify differences in UV exposure between patients with high- and low-risk phenotypes.