MISSENSE MUTATIONS IN SMOH IN SPORADIC BASAL-CELL CARCINOMAS OF THE SKIN AND PRIMITIVE NEUROECTODERMAL TUMORS OF THE CENTRAL-NERVOUS-SYSTEM

About one-third of sporadic basal cell carcinomas (BCCs) of the skin a nd 10-15% of primitive neuroectodermal tumors (PNETs) of the central n ervous system show mutations in the PTCH tumor suppressor gene. The PT CH gene product (Ptch) functions as a transmembrane receptor for the S onic hedgehog protein (Shh) and interacts with another transmembrane p rotein called Smoh. To further elucidate the significance of alteratio ns in the Shh signaling pathway, we investigated 31 sporadic BCCs and 15 PNETs for the mutation and/or expression of SMOH, PTCH, SHH, and GL I1. In addition, we fine-mapped the SMOH gene locus by fluorescence in situ hybridization to chromosomal band 7q32. Mutational analysis iden tified four BCCs with somatic missense mutations in SMOH affecting cod on 535 (TGG double right arrow TTG: Trp double right arrow Leu) in thr ee tumors and codon 199 (CGG double right arrow TGG: Arg double right arrow Trp) in one tumor. A missense mutation at codon 533 (AGC double right arrow AAC: Ser double right arrow Asn) was found in one PNET. PT CH mutations were detected in eight BCCs and one PNET. Two BCCs demons trated mutations in both SMOH and PTCH. The majority of tumors showed an increased expression of SMOH, PTCH, and GLI1 transcripts as compare d with that of normal skin and nonneoplastic brain tissue, respectivel y. In contrast, only one BCC and one PNET expressed SHH mRNA at levels detectable by reverse transcription-PCR, and no SHH gene mutations we re found. In summary, our results indicate that both PTCH and SMOH rep resent important targets for genetic alterations in sporadic BCCs and PNETs.