Original ArticlesBiallelic PTCH1 Inactivation Is a Dominant Genomic Change in Sporadic Keratocystic Odontogenic TumorsStojanov, Ivan J. DMD*,†; Schaefer, Inga-Marie MD‡; Menon, Reshma S. BDS, DMSc§; Wasman, Jay MD∥; Gokozan, Hamza N. MD∥; Garcia, Elizabeth P. PhD‡; Baur, Dale A. DDS¶; Woo, Sook-Bin DMD, MMSc§,#; Sholl, Lynette M. MD‡Author Information Departments of *Oral and Maxillofacial Medicine ¶Oral and Maxillofacial Surgery, Case Western Reserve University School of Dental Medicine †Department of Pathology, Case Western Reserve University School of Medicine ∥Department of Pathology, University Hospitals Cleveland Medical Center, Case Western Reserve University School of Medicine, Cleveland, OH ‡Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School §Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston #Center for Oral Pathology, StrataDx Inc., Lexington, MA Conflicts of Interest and Source of Funding: Supported by grants from the Chalmers J. Lyons Academy of Oral and Maxillofacial Surgery and the HEARTS Foundation. I.-M.S. is supported by a Ruth L. Kirchstein NRSA Institutional Research Training Grant (T32). The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article. Correspondence: Ivan J. Stojanov, DMD, Department of Oral and Maxillofacial Medicine, Case Western Reserve University School of Dental Medicine, 9601 Chester Avenue, Cleveland, OH 44106 (e-mail: [email protected]). The American Journal of Surgical Pathology: April 2020 - Volume 44 - Issue 4 - p 553-560 doi: 10.1097/PAS.0000000000001407 Buy Metrics Abstract Keratocystic odontogenic tumors (KCOTs) are locally aggressive odontogenic neoplasms with recurrence rates of up to 60%. Approximately 5% of KCOTs are associated with nevoid basal cell carcinoma (Gorlin) syndrome and 90% of these show genomic inactivation of the PTCH1 gene encoding Patched 1. Sporadic KCOTs reportedly have PTCH1 mutations in 30% of cases, but previous genomic analyses have been limited by low tumor DNA yield. The aim of this study was to identify recurrent genomic aberrations in sporadic KCOTs using a next-generation sequencing panel with complete exonic coverage of sonic hedgehog (SHH) pathway members PTCH1, SMO, SUFU, GLI1, and GLI2. Included were 44 sporadic KCOTs from 23 female and 21 male patients with a median age of 50 years (range, 10 to 82 y) and located in the mandible (N=33) or maxilla (N=11). Sequencing identified PTCH1 inactivating mutations in 41/44 (93%) cases, with biallelic inactivation in 35 (80%) cases; 9q copy neutral loss of heterozygosity targeting the PTCH1 locus was identified in 15 (34%) cases. No genomic aberrations were identified in other sequenced SHH pathway members. In summary, we demonstrate PTCH1 inactivating mutations in 93% of sporadic KCOTs, indicating that SHH pathway alterations are a near-universal event in these benign but locally aggressive neoplasms. The high frequency of complete PTCH1 loss of function may provide a rational target for SHH pathway inhibitors to be explored in future studies. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.