Studies on basal cell carcinoma with emphasis on the role of the human homologue of the Drosophila patched gene

Basal cell cancer (BCC) is the most common cancer in the Western world. Although BCCs hardly ever metastasize, invasive growth may cause considerable local tissue destruction. Ultraviolet radiation (WR) is presumed to be the predominant environmental factor. BCCs mainly occur as sporadic tumors but also in a hereditary form in Nevoid Basal Cell Carcinoma Syndrome (NBCCS). NBCCS is an autosomal dominant disorder characterized by multiple, recurring BCCs, general cancer susceptibility and developmental abnormalities. In this thesis biological and genetic factors involved in growth and development of BCCs were studied. We found that stromelysin 3 (ST3) expression is a typical feature of the mesenchyme surrounding BCC tumor cells. The ST3 expression strongly correlates with the invasiveness of the tumor and the expression of collagen, indicating an important role of ST3 in the development of fibrosis in BCCs. Studies of Swedish NBCCS families yielded information from critical recombinants which together with loss of heterozygosity (LOH) in a hereditary cardiac fibroma localized the NBCCS gene to chromosome 9q22.3 between the microsatellite markers D9S280 and D9S287. Subsequently, the human homologue (PTCH) of Drosophila patched, identified as the NBCCS gene, was screened by Single Strand Conformational Polymorphism (SSCP) and PTCH mutations were found in NBCCS families, sporadic and hereditary BCCs. Most mutations resulted in a truncated protein and typical WR-induced mutations were identified. Irrespective of histological subtype PTCH mRNA was consistently overexpressed in tumor cells in all BCCs examined. In contrast, p53 immunostaining in the same BCCs was variable. Consistent overexpression of PTCH mRNA was identified in the benign hair follicle-derived tumor, trichoepithelioma, (TE). A PTCH frameshift mutation and in-frame somatic deletions were identified in TEs suggesting a common pathogenic pathway for histopathologically similar but prognostically distinct skin tumors. Overall, these results support the presence of a gatekeeper mechanism in multistep skin tumorigenesis represented by an alteration in the PTCH signaling pathway.