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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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‘Pituitary tumours’ is an umbrella term for various tumours originating from different regions of the hypothalamic–pituitary system. The vast majority of pituitary tumours are pituitary adenomas, also recently referred to as pituitary neuroendocrine tumours. The prevalence of clinically relevant pituitary adenomas is approximately 1 in 1000; other pituitary tumours such as craniopharyngioma and pituicytoma are comparatively very rare. This review addresses the molecular and genetic aspects of pituitary adenomas. We first discuss the germline genetic variants underlying familial pituitary tumours, which account for approximately 5% of all pituitary adenoma cases. This includes variants in established pituitary adenoma/hyperplasia predisposition genes (MEN1, PRKAR1A, AIP, CDKN1B, GPR101, SDHA, SDHB, SDHC, SDHD, SDHAF2) as well as emerging genetic associations. In addition, we discuss McCune–Albright syndrome which lies between the germline and somatic pituitary tumour genes as the causative GNAS mutations are postzygotic rather than being inherited, and the condition is associated with multiglandular features due to the involvement of different cell lines rather than being limited to the pituitary. By contrast, somatic GNAS mutations contribute to sporadic acromegaly. USP8 is the only other gene where somatic driver mutations have been established in sporadic pituitary tumorigenesis. However, there are now known to be a variety of other somatic genetic and molecular changes underpinning sporadic pituitary adenomas which we review here, namely: copy number variation, molecular changes in signalling and hypoxia pathways, epithelial–mesenchymal transition, DNA repair, senescence, the immune microenvironment and epigenetics.
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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.
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Division of Molecular & Clinical Medicine, University of Dundee, Ninewells Hospital & Medical School, Dundee, UK
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target of these miRNAs, and this is in agreement with previous human and mouse studies which have reported that cyclin D1 overexpression occurs in a significant proportion of human sporadic pituitary tumours ( Gazioglu et al. 2007 ) and that miR-15a and
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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
Department of Medical Biotechnologies, University of Siena, Siena, Italy
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will benefit from regular clinical screening which could result in early diagnosis and possibly improved treatment outcomes ( Hernandez-Ramirez et al. 2015 ). In this review, we aim to discuss the genetic causes of familial and sporadic pituitary
