A frequent activated smoothened mutation in sporadic basal cell carcinomas

Basal-cell carcinomas (BCCs) are the most common cancer in Caucasians, It h as been reported that the patched gene is inactivated in 30-40% sporadic BC Cs and 20% sporadic medulloblastomas via loss of heterozygosity and nonsens e mutations. Recently, two activating smoothened mutations have been found in the sporadic basal cell carcinomas. One, at base pair 1604 (G-to-T trans version) of exon 9, changes codon 535 from tryptophan to leucine, and the o ther, at base pair 1685 (G-to-A transition) of exon 10, changes codon 562 f rom arginine to glutamine (Xie et al,, 1998), In our study, 1604G-->T was f ound in 20 out of 97 (20.6%) sporadic BCCs, The high prevalence indicates t hat 1604G is the mutation hot spot in our tumor samples. This mutation was detected in all three histological subtypes of BCCs, suggesting that smooth ened mutation is an early event during the development of the tumor. Our fi nding of a high smoothened mutation rate, together with high frequent patch ed gene mutations reported recently, indicates that activation of the hedge hog signal transduction pathway is the most common and early event in the d evelopment of sporadic BCCs, Additionally, to determine whether smoothened, like patched, is also involved in the carcinogenesis of medulloblastomas, we screened medulloblastoma samples for these two mutations by restriction analysis. We have found the 1604G-->T mutation in 1 out of 21 medulloblasto mas. This result confirmed smoothened gene involvement in the carcinogenesi s of medulloblastoma.