Genetic basis of calcifying cystic odontogenic tumors
June
Genetic basis of calcifying cystic odontogenic tumors
Akane Yukimori 0 1
Yu Oikawa 1
Kei-ichi Morita 1
Chi Thi Kim Nguyen 0 1
Hiroyuki Harada 1
Satoshi Yamaguchi 1
Kou Kayamori 0 1
Akira Yamaguchi 1
Tohru Ikeda 0 1
Kei Sakamoto 0 1
0 Department of Oral Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University , Tokyo , Japan , 2 Department of Oral and Maxillofacial Surgery, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University , Tokyo , Japan , 3 Department of Maxillofacial Surgery, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University , Tokyo , Japan , 4 Department of Bioresource Research Center, Tokyo Medical and Dental University , Tokyo , Japan , 5 Department of Oral Health Science Center, Tokyo Dental College , Tokyo , Japan
1 Editor: Wayne A. Phillips, Peter MacCallum Cancer Centre , AUSTRALIA
Calcifying cystic odontogenic tumors (CCOTs) are benign cystic tumors that form abnormally keratinized ghost cells. Mutations in CTNNB1, which encodes beta-catenin, have been implicated in the development of these tumors, but a causal relationship has not been definitively established. Thus, mutational hot spots in 50 cancer genes were examined by targeted next-generation sequencing in 11 samples of CCOT. Mutations in CTNNB1, but not in other genes, were observed in 10 of 11 cases. These mutations constitutively activate beta-catenin signaling by abolishing the phosphorylation sites Asp32, Ser33, or Ser37, and are similar to those reported in pilomatrixoma and adamantinomatous craniopharyngioma. In contrast, BRAF or NRAS mutations were observed in 12 and two control samples of ameloblastoma, respectively. In HEK293 cells, overexpression of mutated CTNNB1 also upregulated hair keratin, a marker of ghost cells. Furthermore, ghost cells were present in two cases of ameloblastoma with BRAF and CTNNB1 mutations, indicating that ghost cells form due to mutations in CTNNB1. The data suggest that mutations in CTNNB1 are the major driver mutations of CCOT, and that CCOT is the genetic analog of pilomatrixoma and adamantinomatous craniopharyngioma in odontogenic tissue.
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Data Availability Statement: All relevant data are
within the paper and its Supporting Information
files.
Funding: This work was supported by grants-in-aid
from the Japanese Ministry of Education, Culture,
Sports, Science and Technology (KAKENHI
25462848 and KAKENHI 16K11438 to KS). The
funder had no role in study design, data collection
and analysis, decision to publish, or preparation of
the manuscript.
Competing interests: The authors have declared that no competing interests exist.
Introduction
Odontogenic tumors develop in tooth-forming tissues in the jaw, or, rarely, in the gingiva.
These tumors form as a wide range of lesions with diverse histological characteristics [
1
],
highlighting the complexity of tooth morphogenesis and formation. Accordingly, the tumors
are classified based on tissue of origin and histological features. For example, ameloblastoma,
the most common odontogenic epithelial tumor, consists of tumor nests that resemble
enamel-forming organs, but do not differentiate further to deposit enamel. Ameloblastoma is
regarded as a true neoplasm, and is characterized by persistent and local infiltration into
surrounding tissue. In contrast, tumors such as odontomas show only minor defects in tooth
formation, and are thought to be hamartomatous lesions.
On the other hand, calcifying cystic odontogenic tumors (CCOT) are unique lesions that
account for only 1±2% of odontogenic tumors. These tumors are characterized by cystic
proliferation of odontogenic epithelium, and occasionally resemble ameloblastoma [
1
], although
some are solid and present mixed histological features [
1, 2
]. The most prominent and
defining microscopic feature is the formation of ghost cells, which are pale, swollen, and
encapsulated, but devoid of nuclei. These cells are thought to form as a consequence of abnormal
keratinization when tumor cells acquire trichogenic potential [3]. Several ways of
subclassifying CCOT have been proposed [
2, 4
]. For example, Praetorius and coworkers [5] classified
these tumors as cysts (Type I) or neoplasms (Type II). Cysts are unilocular, often associated
with odontoma or an unerupted tooth, and are further subtyped as simple unicystic (Type IA),
odontoma-producing (Type IB), or ameloblastomatous proliferating (Type IC). These cystic
lesions are only weakly neoplastic. These lesions were termed calcifying odontogenic cysts in
the 1971- and 1992-editions of the WHO histological typing of odontogenic tumors, and then
termed CCOTs in the 2005-edition. In contrast, solid Type II neoplasms tend to infiltrate
connective tissue, form ameloblastoma-like tumor nests, and are also called dentinogenic ghost
cell tumors in the 2005- and 2017-edition. In the latest 2017-edition, the term `calcifying
odontogenic cyst' was ado (...truncated)