SFE2002 Poster Presentations Endocrine tumours and neoplasia (17 abstracts)
No activating point mutation in Cyclin-Dependent Kinase 4 (CDK4) in pituitary adenomas, insulinomas and Leydig cell tumours
R Bibi 1 , S Diaz-Cano 1 , V Vax 1 , M Gueorguiev 1 , B Kola 1 , B Bressac 2 , G Walker 3 , AB Grossman 1 & M Korbonits 1
1Department of Endocrinology, St. Bartholomew's Hospital, London, UK; 2Service de Génétique, Institut Gustave Roussy, France; 3Human Genetics Laboratory, Queensland Institute of Medical Research, Royal Brisbane Hospital, Brisbane, Australia.
BACKGROUND: Cell cycle dysregulation is one of the defining features of cancer. Cyclin-dependent kinase 4 (CDK4), together with its regulatory subunit Cyclin D, governs cell cycle progression in G1 phase. CDK4 is in turn regulated by cyclin-dependent kinase inhibitors, including p16INK4A (CDKN2A). Dysregulation of the INK4A/CDK4/cyclin D complex has been established in different a variety of types of human tumours. Dominant mutations affecting codon 24 of the CDK4 gene (replacement of Arg24 by Cys or His) renders CDK4 insensitive to p16INK4 inhibition and is responsible formelanoma susceptibility in some kindreds. . However, 'knockin' mice homozygous for the Cdk4R24C mutation were noted to develop multiple neoplasias, especially including endocrine tumours: pituitary adenomas, insulinomas and Leydig cell testicular tumours. We therefore speculated that sporadic human endocrine tumours might harbour such mutations. The aim of the current study was to analyse the CDK4 gene for the two characterised activating mutations; R24C and R24H, in human sporadic pituitary adenomas, insulinomas and Leydig cell tumours. METHODS: We used cDNA extracted from 46 pituitary adenomas, and paired tumorous and neighbouring normal genomic DNA extracted from 15 insulinoma and 6 Leydig cell tumour samples. Genomic DNA from patients with familial melanoma harbouring the R24C or the R24H mutations served as positive controls. All samples were subjected to PCR, mutation-specific restriction digests and sequencing. RESULTS and CONCLUSION: Restriction enzyme and sequence analysis failed to detect mutations at these two sites in the sporadic endocrine tumours including pituitary adenomas, benign or malignant insulinomas and Leydig cell tumours, while the positive controls showed the expected heterozygote patterns. These data suggest that the changes in the regulatory 'hot-spot' on the CDK4 gene, causing various endocrine tumours is Cdk4R24C/R24C mice, are not a major factor in sporadic pituitary, insulin beta-cell or Leydig cell tumorigenesis.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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