Cutaneous basal cell carcinoma (BCC) is the most common cancer among people of European ancestry (Stacey et al., 2009). The primary environmental risk factor for BCC is sun exposure, but genetics also has a substantial role. Some of ... Cutaneous basal cell carcinoma (BCC) is the most common cancer among people of European ancestry (Stacey et al., 2009). The primary environmental risk factor for BCC is sun exposure, but genetics also has a substantial role. Some of the sequence variants that confer susceptibility seem to operate through their association with fair-pigmentation traits common among Europeans, resulting in reduced protection from the damaging effects of ultraviolet (UV) radiation. Other sequence variants have no obvious role in pigmentation or UV susceptibility but instead seem to operate in the contexts of growth and differentiation of the basal layers of the skin (Stacey et al., 2008; Epstein, 2008; Gudbjartsson et al., 2008; Rafnar et al., 2009). See ASIP (600201), TYR (606933), and SHEP5 (227240) for examples of basal cell carcinoma associated with fair skin or sensitivity to sun. Basal cell carcinoma occurs as a feature of multiple syndromes, including basal cell nevus syndrome (BCNS; 109400), Bazex syndrome (301845), Rombo syndrome (180730), Brooke-Spiegler syndrome (605041), Muir-Torre syndrome (158320), and xeroderma pigmentosum (see 278700). Abnormalities in the Hedgehog signaling pathway are found in basal cell carcinomas; see SHH (600725) and SMOH (601500).
Friedman et al. (1993) analyzed 188 human tumor samples for mutations within the catalytic domain of the GAP gene and for mutations within its C-terminal SH2 region. Although no mutations could be demonstrated in the catalytic domain, 3 ... Friedman et al. (1993) analyzed 188 human tumor samples for mutations within the catalytic domain of the GAP gene and for mutations within its C-terminal SH2 region. Although no mutations could be demonstrated in the catalytic domain, 3 different nonsense mutations in the SH2 region were observed in basal cell carcinomas (e.g., 139150.0001). The region in which the mutations were clustered is A/T rich, raising the possibility that UV radiation is a contributing factor. Using single-strand conformation polymorphism (SSCP), Gailani et al. (1996) screened 37 sporadic BCCs for mutations in the PTCH1 gene and found mutations in 16 (e.g., 601309.0009). Variants in 4 of these 16 were also found in constitutional DNA, and each had been found in at least 12% of normal controls. Nine of the 12 tumor-specific alterations were in the remaining allele of tumors with loss of heterozygosity (LOH) for 9q22, and in 3 tumors without LOH a single variant was found. Of 26 sporadic BCC screened by Aszterbaum et al. (1998) for mutations in PTCH1, 3 had PTCH1 mutations (e.g., 601309.0010), each in a different exon of the gene. Each of these 3 had sustained deletion of the second allele. Aszterbaum et al. (1998) concluded that PTCH1 acts as a classic tumor suppressor gene, requiring 2 'hits' for tumorigenesis in at least some BCC. Using SSCP and heteroduplex analysis, Smyth et al. (1999) identified a nucleotide substitution in the splice donor site of exon 20 of the PTCH2 gene (603673.0002) in a basal cell carcinoma.