Germline and mosaic mutations causing pituitary tumours: genetic and molecular aspects

Abstract

While 95% of pituitary adenomas arise sporadically without a known inheritable predisposing mutation, in about 5% of the cases they can arise in a familial setting, either isolated (familial isolated pituitary adenoma or FIPA) or as part of a syndrome. FIPA is caused, in 15–30% of all kindreds, by inactivating mutations in the AIP gene, encoding a co-chaperone with a vast array of interacting partners and causing most commonly growth hormone excess. While the mechanisms linking AIP with pituitary tumorigenesis have not been fully understood, they are likely to involve several pathways, including the cAMP-dependent protein kinase A pathway via defective G inhibitory protein signalling or altered interaction with phosphodiesterases. The cAMP pathway is also affected by other conditions predisposing to pituitary tumours, including X-linked acrogigantism caused by duplications of the GPR101 gene, encoding an orphan G stimulatory protein-coupled receptor. Activating mosaic mutations in the GNAS gene, coding for the Gα stimulatory protein, cause McCune–Albright syndrome, while inactivating mutations in the regulatory type 1α subunit of protein kinase A represent the most frequent genetic cause of Carney complex, a syndromic condition with multi-organ manifestations also involving the pituitary gland. In this review, we discuss the genetic and molecular aspects of isolated and syndromic familial pituitary adenomas due to germline or mosaic mutations, including those secondary to AIP and GPR101 mutations, multiple endocrine neoplasia type 1 and 4, Carney complex, McCune–Albright syndrome, DICER1 syndrome and mutations in the SDHx genes underlying the association of familial paragangliomas and phaeochromocytomas with pituitary adenomas.

Clinical and Molecular Update on Genetic Causes of Pituitary Adenomas

“…Expression of p27 is also regulated by menin suggesting that mechanisms of tumorogenesis of MEN1 and 4 may be interconnected [51]. To date, 42 cases with 17 different mutations have been reported, the majority of them being missense, but also frameshift and nonsense mutations [48,52]. They generally lead to faster p27 degradation, reduced binding to interacting partners and decreased nuclear translocation of p27 [51].…”

Clinical genetic testing in endocrinology: Current concepts and contemporary challenges

“…Monogenic endocrine syndromes may also occur in the absence of an inherited defect due to de novo mutations (ie mutations arising during parental gametogenesis, or postzygotically in the developing embryo). For example, the majority of cases of MEN2B and X‐linked acrogigantism (XLAG) result from such de novo genetic events (Table ) …”

“…For example, the majority of cases of MEN2B and X-linked acrogigantism (XLAG) result from such de novo genetic events (Table 1). [15][16][17]…”

Clinical Relevance of Genetic Analysis in Patients With Pituitary Adenomas: A Systematic Review

“…The genes of interest include the MEN1, CDKN1B, CDKN2C, PRKAR1A, PRKACA, PRKACB, SDHx, and AIP genes and microduplications of Xq26.3. Due to insufficient evidence in literature for GPR101 allelic variants in the tumorigenesis of PA (15)(16)(17)(18)(19)(20)(21), studies on these variants were excluded from further review. Since the focus of this review is on patients with sporadically occurring PA, studies including patients with clear syndromic features suggestive for a certain genomic mutation were excluded.…”