Genetic basis of calcifying cystic odontogenic tumors

PLOS ONE, Dec 2019

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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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. - 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)


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Akane Yukimori, Yu Oikawa, Kei-ichi Morita, Chi Thi Kim Nguyen, Hiroyuki Harada, Satoshi Yamaguchi, Kou Kayamori, Akira Yamaguchi, Tohru Ikeda, Kei Sakamoto. Genetic basis of calcifying cystic odontogenic tumors, PLOS ONE, 2017, Volume 12, Issue 6, DOI: 10.1371/journal.pone.0180224