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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 through the G1 phase. Cyclin-dependent kinase inhibitors, including p16(INK4A) (encoded by CDKN2A), in turn regulate CDK4. In particular, dysregulation of the p16/CDK4/cyclin D complex has been established in a variety of types of human tumours. Dominant activating mutations affecting codon 24 of the CDK4 gene (replacement of Arg24 by Cys or His) render CDK4 insensitive to p16(INK4) inhibition and are responsible for melanoma susceptibility in some kindreds. However, 'knock-in' mice homozygous for the CDK4(R24C) mutation were noted to develop multiple neoplasia, most commonly including endocrine tumours: pituitary adenomas, insulinomas and Leydig cell testicular tumours. We therefore speculated that sporadic human endocrine tumours might also harbour such mutations. The aim of the current study was to analyze the CDK4 gene for the two characterized activating mutations, R24C and R24H, in sporadic human pituitary adenomas, insulinomas and Leydig cell tumours. We used DNA extracted from 61 pituitary adenomas, and paired tumorous and neighboring normal genomic DNA extracted from 14 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/or sequencing. Both methodologies failed to detect mutations at these two sites in any of the sporadic endocrine tumours including pituitary adenomas, benign or malignant insulinomas or Leydig cell tumours, while the positive controls showed the expected heterozygote patterns. Protein expression of CDK4 was demonstrated by immunohistochemistry and Western blotting in pituitary and pancreatic samples. These data suggest that the changes in the regulatory 'hot-spot' on the CDK4 gene, causing various endocrine tumours in CDK4(R24C/R24C )mice, are not a major factor in sporadic pituitary, insulin beta-cell or Leydig cell tumorigenesis.
South Australian Adult Genetics Unit, Royal Adelaide Hospital, Adelaide, Australia
Adelaide Medical School, University of Adelaide, Adelaide, Australia
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Garvan Institute of Medical Research, Sydney, NSW, Australia
St Vincent’s Clinical School, University of New South Wales, Sydney, NSW, Australia
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St Vincent’s Clinical School, University of New South Wales, Sydney, NSW, Australia
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Academy for Medical Education, Faculty of Medicine, the University of Queensland, Brisbane, Australia
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Garvan Institute of Medical Research, Sydney, NSW, Australia
St Vincent’s Clinical School, University of New South Wales, Sydney, NSW, Australia
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in PA predisposition genes, followed by the various somatic aberrations found in sporadic PAs. Citations have been selected throughout the review to showcase Australian contributions to the pituitary tumour literature in this special issue
Department of Medical Biotechnologies, University of Siena, Siena, Italy
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regulating appetite and energy metabolism. While GPR101 was found to be significantly overexpressed in the pituitary tumours of XLAG patients, it was not expressed in sporadic somatotroph PAs or in the adult human pituitary gland ( Trivellin et al. 2014
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The pathogenesis of sporadic pituitary tumours remains elusive. Recently, a new candidate gene has been described which is able to induce pituitary cell transformation, and the expression of which appears to be strongly correlated with pituitary tumorigenesis. The so-called pituitary tumour transforming gene (PTTG) encodes a 23 kDa, 202 amino acid protein, and is located on chromosome 5q33, a locus previously associated with recurrent lung cancer and acute myelogenous leukaemias. Although the precise function of PTTG protein is unknown, in vitro experiments have demonstrated that it is capable of inducing fibroblast growth factor (FGF) expression. Mutation of the two proline-rich domains of the PTTG protein has also been shown to abolish subsequent FGF induction. Furthermore, in patients with pituitary adenomas, serum FGF concentrations fall post-operatively after successful excision of the tumour.
Centro de Microscopia Electrónica, Facultad de Ciencias Médicas, Universidad Nacional de Córdoba, Córdoba, Argentina
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Centro de Microscopia Electrónica, Facultad de Ciencias Médicas, Universidad Nacional de Córdoba, Córdoba, Argentina
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Centro de Microscopia Electrónica, Facultad de Ciencias Médicas, Universidad Nacional de Córdoba, Córdoba, Argentina
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Centro de Microscopia Electrónica, Facultad de Ciencias Médicas, Universidad Nacional de Córdoba, Córdoba, Argentina
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Introduction Pituitary neuroendocrine tumours (PitNETs) are frequent neoplasms and account for 15% of all intracranial tumours ( Hauser et al. 2019 ). They exhibit a wide range of clinical behaviours, from benign to aggressive, which are
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Division of Molecular & Clinical Medicine, University of Dundee, Ninewells Hospital & Medical School, Dundee, UK
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studies, which have revealed changes in their expression ( Wierinckx et al. 2017 ). For example, sporadic human pituitary tumours have been reported to have altered expression of multiple miRNAs, when compared to normal pituitary tissue ( Bottoni et al
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neoplasias raising the possibility that they represent a tumour-initiating cell population. The elucidation of the mechanisms underlying pituitary stem cell (PSC) self-renewal, differentiation and programmed death may lead to a greater understanding of
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in AIP gene has also been described in sporadic pituitary tumour patients, explained by low penetrance rather than de novo mutations in these families ( Leontiou et al . 2008 , Jaffrain-Rea et al . 2013 , Hernández-Ramírez et al . 2015
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MD , Jenkinson S, Pistorello M, Boscaro M, Scanarini M, McTernan P, Perrett CW, Thakker RV & Clayton RN 1994 Molecular genetic studies of sporadic pituitary tumors. Journal of Clinical Endocrinology and Metabolism 78 387 –392
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inherited endocrine syndromes Model type Heterozygous phenotype Homozygous phenotype References Disorder MEN1 Conventional knockout Tumours of pancreas, parathyroid, pituitary, gonads, adrenals, thyroid; lipomas Embryonic lethal; developmental delay
