Odontogenic tumors represent a spectrum of entities with differing morphologies, clinical presentations and treatments, despite commonalities in association with tooth development and anatomy. The complexity of this classification system is challenging for most pathologists, who rarely see these tumors, and the treatment options are largely limited to the extent of surgery, which can result in disfigurement, create functional problems with speech and swallowing, and is not always curative. Recent studies suggest that there are recurrent genomic events in at least some of these tumors. We have discovered activating mutations in SMO (most commonly SMO-L412F), part of the Hedgehog pathway, and in the mitogen-activated protein kinase (MAPK) pathway (most commonly BRAF-V600E) in over 80% of ameloblastomas. Others had previously found PTCH1 germline inactivation, also part of the Hedgehog pathway, in keratocystic odontogenic tumors associated with Gorlin syndrome (nevoid basal cell carcinoma syndrome). These pathways are druggable and we hypothesize that a new paradigm for the diagnostic classification and treatment of odontogenic tumors can be generated with genetic analysis. We will conduct whole-exome sequencing and transcriptome sequencing of odontogenic tumors, focusing on ameloblastoma, keratocystic odontogenic tumors and other morphologically-similar diagnoses, to identify driver mutations and oncogenic pathways. Using both the mutation and expression profiles, we will create a novel classification system for odontogenic neoplasms. We will create multiple new ameloblastoma cell lines from patient material bearing recurrent driver mutations, including BRAF, SMO, KRAS, and FGFR2. These new cell culture models will enable us to examine the response to gene targeted therapies, as well as to anticipate likely mechanisms of therapy resistance.

Public Health Relevance

Odontogenic tumors are neoplasms that are derived from the tooth forming tissue. Conventional classification is based on morphology and clinical treatment is largely limited to surgical therapy, which can be disfiguring, create functional problems with speech and swallowing, and is not always curative. Based on our recent findings of targetable mutations in subsets of these tumors, we hypothesize that a new paradigm for the medical management of odontogenic tumors, particularly ameloblastoma, can be generated with genetic analysis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE026502-03
Application #
9720877
Study Section
Cancer Biomarkers Study Section (CBSS)
Program Officer
Wang, Chiayeng
Project Start
2017-07-12
Project End
2022-06-30
Budget Start
2019-07-01
Budget End
2020-06-30
Support Year
3
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Stanford University
Department
Pathology
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305