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Novel Genetic Causes of Pituitary Adenomas Francisca Caimari and Marta Korbonits

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Novel Genetic Causes of Pituitary Adenomas Francisca Caimari and Marta� Korbonits CCR FOCUS CCR Focus Novel Genetic Causes of Pituitary Adenomas Francisca Caimari and Marta Korbonits Abstract Recently, a number of novel genetic alterations have been dromes, Carney complex, and McCune-Albright syndrome. Pitu- identified that predispose individuals to pituitary adenomas. itary tumors have also been described in association with neu- Clinically relevant pituitary adenomas are relatively common, rofibromatosis type 1, DICER1 syndrome, and SDHx mutations. present in 0.1% of the general population. They are mostly benign Pituitary adenomas with no other associated tumors have been monoclonal neoplasms that arise from any of the five hormone- described as familial isolated pituitary adenomas. Patients with secreting cell types of the anterior lobe of the pituitary gland, and AIP or GPR101 mutations often present with pituitary gigantism cause disease due to hormonal alterations and local space-occu- either in a familial or simplex setting. GNAS and GPR101 muta- pying effects. The pathomechanism of pituitary adenomas tions that arise in early embryonic age can lead to somatic includes alterations in cell-cycle regulation and growth factor mosaicism involving the pituitary gland and resulting in growth signaling, which are mostly due to epigenetic changes; somatic hormone excess. Senescence has been suggested as the key mech- and especially germline mutations occur more rarely. A significant anism protecting pituitary adenomas turning malignant in proportion of growth hormone- and adrenocorticotrophin- the overwhelming majority of cases. Here we briefly summarize secreting adenomas have activating somatic mutations in the the genetic background of pituitary adenomas, with an emphasis GNAS and USP8 genes, respectively. Rarely, germline mutations on the recent developments in this field. Clin Cancer Res; 22(20); predispose to pituitary tumorigenesis, often in a familial setting. 5030–42. Ó2016 AACR. Classical tumor predisposition syndromes include multiple See all articles in this CCR Focus section, "Endocrine Cancers: endocrine neoplasia type 1 (MEN1) and type 4 (MEN4) syn- Revising Paradigms." Introduction Data derived from autopsies and radiologic imaging studies have shown that pituitary adenomas are relatively common, The pituitary gland consists of an anterior lobe of epithelial estimated to be present overall in 17% of the general population origin and a posterior lobe of neuronal origin. The main cell (2, 3). Although most of these small lesions are incidental find- types of the anterior lobe are the hormone-secreting cells [growth ings, with no obvious clinical impact (3), clinically relevant hormone (GH), prolactin, adrenocorticotrophin (ACTH), thyro- pituitary adenomas are present in 0.1% of the general population, tropin (TSH), or gonadotrophin (LH and FSH)] and the folli- and they represent the third most-frequent intracranial tumor culostellate cells. The term "pituitary adenoma" is attributed to type after meningiomas and gliomas (4). the usually benign tumors arising from the hormone-secreting Pituitary adenomas are monoclonal neoplasms in origin cells of the anterior pituitary. Typically, pituitary adenomas (5). A number of different molecular mechanisms that lead are classified as either functioning pituitary adenomas with to pituitary adenomas have been identified,althoughinthe characteristic clinical symptoms, such as acromegaly or Cushing majority of the sporadic cases, the exact molecular patho- disease, or clinically nonfunctioning pituitary adenomas genesis remains unknown. Factors hypothesized to contrib- (NFPA), usually arising from cells secreting LH and FSH. These ute to pituitary neoplasia initiation and proliferation include adenomas generally present as slowly growing lesions with altered growth factors and cell-cycle regulators that are the low mitotic rate and Ki-67 labeling index (1). Symptoms are result of epigenetic changes (6), abnormal hormonal milieu, present due to hormonal disturbances, hypersecretion or lack of abnormal intrapituitary microenvironment (7), and inherited pituitary hormones, and compression symptoms that are sec- or somatic mutations (Fig. 1). The role of environmental ondary to local invasion and lead to hypopituitarism and visual factors remains questionable (8–10). In the following brief field defects. overview of the underlying pathomechanisms, we will con- centrate on germline and somatic mutations that lead to pituitary adenomas. Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary Uni- versity of London, London, United Kingdom. Germline Mutations Corresponding Author: Marta Korbonits, Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Familial pituitary adenomas can be divided into (i) an isolated Dentistry, Queen Mary University of London, London EC1M 6BQ, United King- group, in which no other organs are involved in addition to the dom. Phone: 4420-7882-6238; Fax: 4420-7882-6197; E-mail: pituitary gland, and (ii) a syndromic group, which includes [email protected] multiple endocrine neoplasia type 1 (MEN1), MEN4, Carney doi: 10.1158/1078-0432.CCR-16-0452 complex, DICER1 syndrome, SDHx gene–associated syndromes, Ó2016 American Association for Cancer Research. and neurofibromatosis type 1 syndrome (Fig. 1; Table 1). Familial 5030 Clin Cancer Res; 22(20) October 15, 2016 Downloaded from clincancerres.aacrjournals.org on September 23, 2021. © 2016 American Association for Cancer Research. Genetics of Pituitary Tumors Pituitary adenomas Germline 5% mutations Carney 3P Neurofibro- DICER1 FIPA MEN1/4 complex association matosis type 1 syndrome AIP MEN1 PRKAR1A SDHA/B/C/D NF1 DICER1 GPR101 CDKN1B PRKACB 2q16 SDHAF2 Sporadic pituitary adenomas with no ~60% known Somatic Mosaic genetic ~40% <1% background mutations mutations All types of Oncocytic McCune- Cushing GH tumors pituitary pituitary Albright XLAG disease adenomas adenomas syndrome PIK3CA Complex I GNAS (30%) USP8 (60%) GNAS GPR101 (30%) genes (60%) © 2016 American Association for Cancer Research Figure 1. Germline, somatic, and mosaic mutations identified in familial and sporadic pituitary adenomas. Mosaic mutations denote the presence of two or more populations of cells with different genotypes in one individual who has developed from a single fertilized egg. 3P association, paraganglioma/ pheochromocytome/pituitary adenoma; FIPA, familial isolated pituitary adenoma; MEN, multiple endocrine neoplasia; NF1, neurofibromatosis type 1. isolated pituitary adenoma (FIPA) is the most common type AIP mutations. The prevalence of AIP mutations in FIPA families followed by MEN1, which together represent 5% to 7% of pati- is 17% to 20% (15, 16), whereas in sporadic cases, it ranges ents with pituitary adenomas (11). between 3.6% (unselected pituitary adenoma patients) and 10% to 20% (pediatric pituitary adenoma cases; refs. 17, 18). About Isolated pituitary adenomas 50% of AIP mutation–positive probands have a positive family FIPA is defined by the presence of pituitary adenomas in two history (16), whereas mutations in the other half are found as a or more family members with no other syndromic features germline mutation in sporadically diagnosed pituitary adenoma present (12). FIPA is a heterogeneous condition that includes patients, so-called "simplex cases." The lack of apparent family patients with mutations in the aryl hydrocarbon receptor– history in the latter group is due to low penetrance, as de novo interacting protein (AIP) gene (13), patients with X-linked mutations have only been found in two cases (19, 20). Pene- acrogigantism (XLAG) due to duplication of GPR101 (14), and trance in AIP-mutated families is incomplete (Fig. 2A): only patients with a family history of pituitary adenomas with no every fifth mutation carrier manifests the disease. The age of known genetic cause. Patients with AIP or GPR101 mutations or onset is also characteristic; the disease usually manifests in the with AIP and GPR101-negative FIPA do not present with other second decade of life and almost all cases are diagnosed before types of tumors, hence the name "isolated" pituitary adenomas. the age of 30 years (15, 16, 21, 22). Not all cases grouped under this category have a known family AIP encodes a 330 amino acid protein acting as a tumor history, either due to low penetrance (such as in AIP mutation– suppressor. It has a wide tissue distribution; in the normal human positive simplex cases) or due to de novo mutations (most cases pituitary, it is expressed in GH cells (somatotroph cells) and of XLAG). prolactin-secreting cells (23). Lack of interaction with cell type– www.aacrjournals.org Clin Cancer Res; 22(20) October 15, 2016 5031 Downloaded from clincancerres.aacrjournals.org on September 23, 2021. © 2016 American Association for Cancer Research. CCR FOCUS Table 1. Germline and mosaic mutations predisposing to pituitary adenomas Genetic alteration (inheritance Syndrome pattern) Function Location Penetrance Prevalencec Main clinical characteristics Carney complex PRKAR1A (AD) TSG 17q24.2 >95% overall, 80% Unknown Skin pigmentation; myxomas; thyroid, for GH excess testis and adrenal tumors, as well as somatotroph hyperplasia or adenomas 2p16 locus — 2p16 Unknown Unknown Less severe Carney complex phenotype, (unknown mostly in sporadic cases gene) PRKACB Oncogene 1p31.1 Unknown One case described Described in one case with Carney complex (31) DICER1 DICER1 (AD) TSG 14q32.13 Unknown, <1% Unknown Pituitary
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