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Editorial |
Department of Medicine, Cedars-Sinai Medical Center, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, California 90048
Address all correspondence and requests for reprints to: Shlomo Melmed, M.D., 8700 Beverly Boulevard, Room 2015, Los Angeles, California 90048. E-mail: melmed{at}cshs.org.
Anterior pituitary cells secreting the trophic hormones GH, prolactin (PRL), ACTH, TSH, FSH, and LH are committed early in embryonic life to synthesize highly differentiated gene products (1). Pituitary tumors may arise from specific anterior pituitary cell types. These commonly benign monoclonal neoplasms may be functional, i.e. hypersecreting one or more trophic hormones, or nonfunctional arising primarily from nonsecreting gonadotroph or null cells (2). The pathogenesis of these tumors has been ascribed to several causes (3, 4).
Early intrapituitary changes leading to tumor formation include intrinsic cell alterations and altered availability of endocrine or paracrine regulatory factors. These disruptions lead to unrestrained cell proliferation as well as hormone hypersecretion. Thus, hypothalamic hormone excess may lead to pituitary hyperplasia, adenoma formation, and hormone hypersecretion, as exemplified by patients with carcinoid tumors elaborating excessive tumor-derived ectopic GHRH (5). Disruption of peripheral hormone negative feedback inhibition (e.g. by target organ ablation) may lead to respective trophic hormone cell hyperplasia and sometimes to adenoma formation, as seen with long-standing hypothyroidism or after adrenal gland resection. Several intrapituitary growth factor and oncogene activations, or dysfunctions of their cognate receptor signaling, have been reported in both human and transgenic mouse models for this disorder (6, 7, 8, 9, 10, 11). Loss of heterozygosity (LOH), specifically at sites on 11q and 13q, and loss of suppressor genes have been reported in subsets of sporadic pituitary tumors (12, 13, 14, 15, 16). Thus, multiple factors contribute to the autonomous growth and unrestrained replication of anterior pituitary tumors. These include altered chromosome stability, cell cycle disruption, growth factor receptor dysfunction, gsp mutation, estrogen stimulation, oncogene activation, loss of tumor suppressor activity, and aberrant hypothalamic hormone signaling.
Rarely, pituitary tumors arise as components of well-defined familial syndromes. Multiple endocrine neoplasia I has been ascribed to loss of the menin tumor suppressor gene (17). These patients exhibit pancreatic, pituitary, and/or parathyroid gland hypersecretion with high familial penetrance. The McCune-Albright syndrome, associated with constitutive ligand-independent GNASI activation (chromosome 20q13.2), comprises precocious puberty, hyperthyroidism, skin and bone lesions, and GH or PRL or ACTH-secreting pituitary adenomas (18). Carney syndrome is a rare familial disorder, with about 500 registered patients. The syndrome comprises cardiac myxomas, pigmented skin lesions, adrenal tumors, as well as GH-secreting pituitary adenomas (19). This condition exhibits genetic heterogeneity and maps to chromosomes 2p16 or 17q24. The CNC1 gene encodes for PRKAR1
, and mutations lead to enhanced tumor protein kinase A responses (20).
The syndrome of isolated familial acromegaly (somatotropinomas) has been recognized as a very rare familial disorder, and less than 40 families have been reported (21, 22). Tumors associated with this condition occur more commonly in young patients, and about 25% are reported as giants. Although these families have heretofore exhibited no obvious genetic mutation, LOH on chromosome 11q13, distinct from multiple endocrine neoplasia I, has been observed and led to the search for relevant tumor suppressor genes at this locus region. In contrast to findings in the isolated familial form of acromegaly, the overwhelming majority of patients with secreting and nonsecreting pituitary tumors that arise sporadically exhibit no obvious familial pattern (23).
Three papers in this issue of JCEM (24, 25, 26) as well as four recent publications (27, 28, 29, 30) report results of genetic analyses of patients with pituitary tumors for AIP gene mutations. The aryl hydrocarbon receptor (AHR) binds to carcinogenic hydrocarbons, including dioxin (31). AHR interaction protein (AIP), is a 330-amino acid chaperone protein that complexes with aryl hydrocarbons, heat shock proteins (HSP90), and the AHR (32, 33). AIP is a ligand-activated transcription factor, but it is not a member of the steroid receptor superfamily. The protein is an immunophilin-like molecule with FKBP homology and also binds and inactivates phosphodiesterase (PDE4A5), which hydrolyzes cAMP (34).
Recently, Vierimaa et al. (27) described a nonsense Q14X AIP mutation that segregated with acromegaly in members of two Finnish families with a predisposition to GH and PRL-secreting pituitary adenomas. Of seven family members harboring mutations, six were less than 35 yr of age. An R340X AIP mutation was also identified in an Italian family with acromegaly. In a total of 15 families now reported, over 10 different germline mutations have been identified. In contrast, mutations were not detected in German and Turkish subjects with familial somatotropinomas. Overall, germline AIP mutations appear to be prevalent in about 15% of families with isolated familial acromegaly (25, 26, 27, 29).
Unlike the prevalence of AIP genetic abnormalities described in familial acromegaly, germline AIP mutations appear to occur at a very low prevalence in subjects harboring sporadic pituitary tumors. In published reports now encompassing a total of 565 patients harboring sporadic pituitary tumors, germline mutations have very rarely been detected. These include two of 113 U.S. patients (30), one of 122 Polish patients, and two of 27 young German patients. In other reports, none of 284 patients from Western Europe, Japan, and the United States were found to harbor a germline mutation. Of note, Yu et al. (28) assessed for the presence of the original three germline mutations reported. In contrast, in 10 Finnish patients with sporadic acromegaly, four were found to harbor the Q14X germline mutation (27, 30). The geographic differences in these results may imply an ascertainment bias or an environmental difference in disease penetrance in the study population. Given the difficulty in obtaining accurate family histories for these rare benign tumors, which often remain undetected until autopsy, there is the possibility that some reported sporadic tumors are actually familial in nature. Careful family evaluations will be required to definitively exclude this possibility.
How Could Mutated AIP Lead to Formation of a Pituitary Tumor?
Because intrapituitary cAMP abundance is vital for controlling both cell replication and hormone synthesis (35), disrupted AIP could lead to elevated cAMP levels and hence promote tumor formation. This hypothesis requires rigorous in vitro and in vivo testing and will certainly add important insights into the biology of pituitary adenomas. The R304X mutation results in disrupted AHR binding, and a recent report has shown that immunoreactive AIP is indeed less abundant in pituitary tumor tissue that exhibits LOH for AIP (30). The observed loss of the wild-type allele in mutation-positive tumors suggests that they are truly null for AIP. This evidence lends credence to the notion that the AIP gene product may exhibit characteristics of a tumor suppressor protein.
The studies thus far reported indicate the presence of AIP germ line mutations in a small (
15%) subset of a very rare Mendelian disorder. Several important sets of experiments are required to satisfy the postulate that AIP disruption leads to pituitary tumor formation. However, ex vivo study of human pituitary tumors is hampered by several limitations. Importantly, the gland itself is inaccessible for readily facile acquisition of normal or tumorous biopsy material. Furthermore, the unique inability to derive functional human pituitary cell lines has necessitated employing murine and rat cell and transgenic models that may not faithfully replicate the human condition. Finally, the highly differentiated nature of each tumor type does not allow for broad generalizations of specific pathological findings. With these constraints in mind, it would be important to establish patterns of AIP gene expression by measuring mRNA and protein expression levels in pituitary tumor samples derived from patients with both sporadic and familial forms of pituitary tumor. Reintroduction of a mutated exogenous AIP construct into pituitary tumor cells and testing resultant tumor growth and hormone secretion would also satisfy a postulate for direct tumor causation. The nonavailability of a differentiated human pituitary cell line will require use of well-known rat or murine pituitary tumor cell lines for these experiments. Given the likelihood for prevalent wild-type AIP expression in most of these lines, results of these experiments will require extrapolation to the human condition with some degree of caution. Recapitulation of in vivo pituitary tumor formation by expressing a mutant AIP transgene in mice should validate the relevance of the mutation for pituitary tumorigenesis. The proposed experiment to express the mutant AIP transgene in vivo is proof of principle; however, the experiment would best be performed with allelic expression of the transgene because overexpression studies may result in a false-positive model of tumorigenesis.
Several unique characteristics of familial pituitary tumor syndromic studies will be challenging for further study of the clinical impact of AIP mutation diagnostic screening (36). This is especially true for familial acromegaly, where affected individuals are young and over 25% have reported gigantism, and these tumors are relatively large, compressing gonadotroph reserve function. Loss of gonadotrope function and resultant early onset hypogonadism may preclude disease transmission to a succeeding generation and hamper genetic analyses. The extremely low frequency of familial pituitary tumors of all types, the small size of affected families, and the low (15%) prevalence of AIP mutations within these families will unfortunately not yet justify use of genetic screening of families for AIP mutations. The high false-positive rate of magnetic resonance image screening for pituitary adenomas also underscores the challenge of employing rarely occurring predisposition markers for pituitary adenomas. Consequently, the relatively low cost and universal availability of accurate biochemical screening tests (e.g. urinary free cortisol levels or serum IGF-I or PRL measurements) does not currently justify recommending AIP genetic screening of families of patients with sporadic hormone-secreting pituitary tumors.
Footnotes
Abbreviations: AHR, Aryl hydrocarbon receptor; AIP, AHR interaction protein; LOH, loss of heterozygosity; PRL, prolactin.
Received March 15, 2007.
Accepted March 16, 2007.
References
, a growth inhibitory gene, in human pituitary adenomas: implications for tumorigenesis. J Clin Endocrinol Metab 87:1262–1267 chain of Gs and stimulate adenylyl cyclase in human pituitary tumours. Nature 340:692–696[CrossRef][Medline]This article has been cited by other articles:
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  S. Melmed Update in Pituitary Disease J. Clin. Endocrinol. Metab., February 1, 2008; 93(2): 331 - 338. [Abstract] [Full Text] [PDF]
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 A. Beckers and A. F Daly The clinical, pathological, and genetic features of familial isolated pituitary adenomas Eur. J. Endocrinol., October 1, 2007; 157(4): 371 - 382. [Abstract] [Full Text] [PDF]
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