Defects of the Carney complex gene (PRKAR1A) in odontogenic tumors

Abstract

The surgical treatment of some odontogenic tumors often leads to tooth and maxillary bone loss as well as facial deformity. Therefore, the identification of genes involved in their pathogenesis may result in alternative molecular therapies. The PRKAR1A gene shows loss of protein expression, as well as somatic mutations in odontogenic myxomas, an odontogenic ectomesenchymal neoplasm. We used a combination of qRT-PCR, immunohistochemistry, LOH analysis and direct sequencing of all PRKAR1A exons to assess if this gene is altered in mixed odontogenic tumors. Thirteen tumors were included, being six ameloblastic fibromas, four ameloblastic fibro-odontomas, one ameloblastic fibrodentinoma and two ameloblastic fibrosarcomas. The epithelial component of the tumors was separated from the mesenchymal by laser microdissection in most of the cases. We also searched for odontogenic pathology in Prkar1a+/− mice. PRKAR1A mRNA/protein expression was decreased in the benign mixed odontogenic tumors in association with LOH at markers around PRKAR1A gene. We also detected a missense and two synonymous mutations, besides two 5’-UTR and four intronic mutations in the mixed odontogenic tumors. Prkar1a+/− mice did not show evidence of odontogenic tumor formation, suggesting that additional genes may be involved in their pathogenesis, at least in rodents. We conclude that the PRKAR1A gene and its locus are altered in mixed odontogenic tumors. PRKAR1A's expression is decreased in a subset of tumors but not in all, and Prkar1a+/− mice do not show abnormalities, suggesting that additional genes play a role in this tumor's pathogenesis.

Odontogenic myxoma: A dual affliction in maxilla and mandible - A case report

“…Identifying pathogenic genes may enable molecular treatments, preventing deformities resulting from surgery. 10…”

PRKAR1A is a functional tumor suppressor inhibiting ERK/Snail/E-cadherin pathway in lung adenocarcinoma

“…PRKAR1A protein insufficiency and PKA dysregulation have been implicated in various types of disorders, including Albright hereditary osteodystrophy (AHO), pseudohypoparathyroidism (PHP), acrodysostosis (ACRDYS)8, and Carney complex9. Interestingly, recent studies also showed that PRKAR1A protein expression level was significantly dysregulated in multiple primary carcinomas and distant metastases, such as cardiac myxomas10, odontogenic myxomas11, anaplastic thyroid carcinomas12, breast cancer13, pediatric pituitary adenomas14, and Schwann cell tumors15.…”