ODONTOGENIC KERATOCYST - THE ROLE OF PTCH1 AND HEDGEHOG SIGNALING IN ITS PATHOGENESIS

Abstract

Objectives Mutations in PTCH1gene, a receptor in the Hedgehog (Hh) signaling, are responsible for Gorlin syndrome (GS) and are related in tumors associated with this syndrome. The aims of this series of studies were to determine the role of PTCH1 mutation and misregulation of the Hh signaling in the pathogenesis of GS-related and sporadic odontogenic keratocysts (OKCs). Findings Based on screening of 73 sporadic and 30 GS-related OKCs, we identified PTCH1 mutations in 35.6% (somatic, 26/73) of sporadic cases and 83.3% (germ-line, 25/30) of GS-related OKCs. However, a much higher mutation rate (79%, 30/38) in sporadic OKCs was detected by analyzing epithelial samples separated from the fibrous capsules. The previously underestimated mutation rate in sporadic cases might be due to the masking effect of the attached stromal tissues. Mutations in other genes of the Hh signaling such as PTCH2, SUFU, and SMO were rare and their pathologic roles in OKC were uncertain. Using whole-exome sequencing (WES), we further characterized the mutational landscape of 5 OKC samples lacking PTCH1 mutation and revealed 22 novel mutations, among which two significantly altered genes (CDON and MAPK1) were predicted to affect Hh signaling activity in two cases. However no recurrent mutations were identified in the WES samples and validation cohort of 10 OKCs. Functional analysis revealed that PTCH1 mutations activated Hh signaling and resulted in aberrant cell proliferation via both classical and non-canonical Hh pathways. Conclusions Our data confirmed the high PTCH1mutation rate in both GS-related and sporadic OKCs. In PTCH1-negative cases, other genetic alterations were rare, but could also be related to Hh signaling. These results suggested that an inhibitor of the Hh pathway may be effective for the treatment of OKCs.