Involvement of PTCH1 mutations in the calcifying epithelial odontogenic tumor

The human homologue of the Drosophila segment polarity gene PTCH1, a tumor suppressor gene within the Sonic Hedgehog pathway has been implicated as the mutation responsible for nevoid basal cell carcinoma syndrome (NBCCS) as well as many other sporadic neoplasms. The calcifying epithelial odontogenic tumor (CEOT) is a rare and aggressive tumor of the jaws. The objective of this study was to investigate the role of the Sonic hedgehog pathway in the pathogenesis of the CEOT. We evaluated the protein distribution of PTCH and the transcription factors Gli1 and Gli2 within seven cases using immunohistochemistry. We also sought to confirm the findings by sequencing the PTCH1 gene from DNA extracted from the paraffin-embedded tissue of these cases. Seven cases of paraffin-embedded CEOT specimens were analyzed with immunohistochemistry. Immunoreactivity for Sonic hedgehog pathway proteins was evaluated using antibodies to the receptor PTCH as well as to the transcription factors Gli1 and Gli2. A keratocystic odontogenic tumor (KOT) from a 12year-old with NBCCS served as our positive control. Normal salivary gland tissue served as our negative control. PTCH gene sequencing was completed using PCR. Immunoreactivity to PTCH was seen in 6/7 cases, to Gli1 in 6/7 cases and to Gli2 in 6/7 cases. All three proteins were positive in the syndromic KOT and all proteins were negative in normal salivary tissue. Gene sequencing revealed five single-nucleotide polymorphisms (SNPs) of which two resulted in missense mutations. A missense mutation was also detected in the KOT. This study is the first to implicate the Sonic hedgehog pathway in the pathogenesis of the CEOT through sequencing. Similar to other odontogenic neoplasms gene mutations in PTCH1 are present in the CEOT.