Abstract
The CABLES1 cell cycle regulator participates in the adrenal–pituitary negative feedback, and its expression is reduced in corticotropinomas, pituitary tumors with a largely unexplained genetic basis. We investigated the presence of CABLES1 mutations/copy number variations (CNVs) and their associated clinical, histopathological and molecular features in patients with Cushing’s disease (CD). Samples from 146 pediatric (118 germline DNA only/28 germline and tumor DNA) and 35 adult (tumor DNA) CD patients were screened for CABLES1 mutations. CNVs were assessed in 116 pediatric CD patients (87 germline DNA only/29 germline and tumor DNA). Four potentially pathogenic missense variants in CABLES1 were identified, two in young adults (c.532G > A, p.E178K and c.718C > T, p.L240F) and two in children (c.935G > A, p.G312D and c.1388A > G, and p.D463G) with CD; no CNVs were found. The four variants affected residues within or close to the predicted cyclin-dependent kinase-3 (CDK3)-binding region of the CABLES1 protein and impaired its ability to block cell growth in a mouse corticotropinoma cell line (AtT20/D16v-F2). The four patients had macroadenomas. We provide evidence for a role of CABLES1 as a novel pituitary tumor-predisposing gene. Its function might link two of the main molecular mechanisms altered in corticotropinomas: the cyclin-dependent kinase/cyclin group of cell cycle regulators and the epidermal growth factor receptor signaling pathway. Further studies are needed to assess the prevalence of CABLES1 mutations among patients with other types of pituitary adenomas and to elucidate the pituitary-specific functions of this gene.
Highlights
In recent years, germline defects in multiple genes have been linked to the pathogenesis of pituitary adenomas, both with syndromic and isolated presentation (Caimari & Korbonits 2016)
In contrast with other types of pituitary tumors, corticotropinomas are infrequent in patients with ‘classic’ multiple endocrine neoplasia and have rarely been described in the setting of familial isolated pituitary adenoma (FIPA) (Stratakis et al 2010, Cazabat et al 2012)
Somatic mutations in the USP8 gene hotspot are highly prevalent among corticotropinomas in adult and pediatric patients, but they have not been detected in other types of pituitary adenomas (PérezRivas et al 2015, Reincke et al 2015)
Summary
Germline defects in multiple genes have been linked to the pathogenesis of pituitary adenomas, both with syndromic and isolated presentation (Caimari & Korbonits 2016). In contrast with other types of pituitary tumors, corticotropinomas are infrequent in patients with ‘classic’ multiple endocrine neoplasia and have rarely been described in the setting of familial isolated pituitary adenoma (FIPA) (Stratakis et al 2010, Cazabat et al 2012). Somatic mutations in the USP8 gene hotspot are highly prevalent among corticotropinomas in adult and pediatric patients, but they have not been detected in other types of pituitary adenomas (PérezRivas et al 2015, Reincke et al 2015). The physiological negative feedback exerted by glucocorticoids on the corticotroph cells is often impaired in corticotropinomas, and, concordantly, CABLES1 protein expression is lost in around half of such tumors (Roussel-Gervais et al 2010, Roussel-Gervais et al 2016). We investigated the presence of CABLES1 gene mutations and copy number variations (CNV) in a large group of patients with Cushing’s disease (CD)
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