Somatic mutations in the components of Hh signaling (PTCH1 and SMO) have been shown to be a major cause of basal cell carcinoma, and dozens of Hh inhibitors have been developed.
The smoothened (SMO) receptor is an essential component of the Sonic hedgehog (SHH) signalling, which is associated with the development of skin basal cell carcinoma (BCC).
Other genotypes, such as the TT in SHH rs104894049331 A/T and the GG in SMOrs41303402rs41303402" genes_norm="5727;6608">385 G/A also statistically raised the risk of BCC, but these associations were weaker.
The constitutive activation of the sonic hedgehog signaling pathway by acquired mutations in the PTCH and SMO genes appears to represent the early basal cell carcinoma developmental determinant.
The immunoexpression of the Shh and Smo proteins significantly increased in the BCC group, as compared with the normal controls (for Shh, the mean intensity was 1.67 in BCC vs. 1.17 in the control group, p < 0.001; for Smo, the mean intensity was 1.46 in BCC vs. 0.99 in the control group, p < 0.001).
In addition to those that are potential germline polymorphisms, we found three SMO missense mutations, and one PTCH1 frameshift mutation that are novel and have not been documented in basal cell carcinoma.
Some tumors exhibiting hedgehog pathway activation such as basal cell cancer frequently harbor PATCHED-ONE (PTCH-1) or SMOOTHENED (SMO) gene mutations.
SMOH mutations were identified in four of the 42 BCCs (10%) while two tumours demonstrated mutations in SUFUH, including one missense mutation and one silent mutation.
70-80% of XP skin cancers exhibit one or several mutations in the P53, PTCH-1, SMO or CDKN2A genes, the type and frequency of mutated genes being different between squamous cell (SCCs) and basal cell carcinomas (BCCs).
Mutational analysis identified four BCCs with somatic missense mutations in SMOH affecting codon 535 (TGG==>TTG: Trp==>Leu) in three tumors and codon 199 (CGG==>TGG: Arg==>Trp) in one tumor.