Research Article: Genetic basis of calcifying cystic odontogenic tumors

Date Published: June 28, 2017

Publisher: Public Library of Science

Author(s): Akane Yukimori, Yu Oikawa, Kei-ichi Morita, Chi Thi Kim Nguyen, Hiroyuki Harada, Satoshi Yamaguchi, Kou Kayamori, Akira Yamaguchi, Tohru Ikeda, Kei Sakamoto, Wayne A. Phillips.


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.

Partial Text

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.

In 10 of 11 archived CCOT samples, mutations were found exclusively in CTNNB1. Similar CTNNB1 mutations have been reported in various cancers such as colorectal or lung adenocarcinoma, but at relatively low frequencies of less than 5% [13], suggesting that such mutations are not essential to many of those tumors. In contrast, the prevalence of somatic CTNNB1 mutations in CCOT, as well as the absence of mutations in other genes, strongly suggests a causal relationship.




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