Abstract
Activating mutations in the RET proto-oncogene are associated with both familial and sporadic medullary thyroid carcinoma (MTC) development; however, the genetic mechanisms underlying MTC tumorigenesis remain largely unknown. Recently, we have identified somatic inactivating mutations in the cell cycle inhibitor gene P18 in human MTC, which coincided with activating RET mutations, suggesting a role for loss of P18 in combination with oncogenic RET in the multistep process of MTC development. Therefore, we crossed transgenic mice expressing oncogenic RET (RET2B) with mice lacking p18 (and p27, another cell cycle inhibitor) and monitored MTC development. RET2B;p18(+/-) mice and RET2B;p18(-/-) mice developed MTC with a highly increased incidence compared with their corresponding single mutant littermates. In addition, expression of oncogenic RET causes an earlier age of onset and larger MTCs in p18(-/-);p27(+/-) mice. In a subset of MTCs of RET2B;p18(+/-)(;p27(+/-)) mice, p18(Ink4c) expression was completely lost. This loss of p18(Ink4c) expression correlated with higher proliferation rates as well as with larger MTCs, indicating that loss of p18 in combination with oncogenic RET not only increases the risk for MTC development but also enhances MTC progression. Our data strongly indicate that oncogenic RET and loss of p18 cooperate in the multistep tumorigenesis of MTC.
Highlights
Multiple endocrine neoplasia type 2 (MEN2) is an autosomal dominantly inherited cancer syndrome, which is mainly characterized by a combination of medullary thyroid carcinoma (MTC) and adrenal pheochromocytoma
We provide experimental evidence that p18 inactivation functionally collaborates with oncogenic RET in murine MTC development
As compared with the single mutant mouse strains, we have found an increased MTC incidence in both RET2B;p18+/À and RET2B;p18À/À mice from 9 months onward
Summary
Multiple endocrine neoplasia type 2 (MEN2) is an autosomal dominantly inherited cancer syndrome, which is mainly characterized by a combination of medullary thyroid carcinoma (MTC) and adrenal pheochromocytoma. MEN2 can be subdivided into MEN2A, MEN2B, and familial MTC. Familial MTC patients solely develop MTC, whereas MEN2A and MEN2B patients may develop, in addition to MTC and pheochromocytoma, other tumors like parathyroid adenomas ( for MEN2A) and mucosal ganglioneuromas ( for MEN2B). MTC originates from the calcitonin-producing neuroendocrine C-cells in the thyroid gland [1]. Current address for D.S. Acton: MucoVax B.V., Leiden, the Netherlands. Current address for D.S. Franklin: Department of Biochemistry, Tulane University School of Medicine, New Orleans, LA. Current address for W. van Veelen: Department of Gastroenterology and Hepatology, Erasmus Medical Center, Rotterdam, the Netherlands
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