role of the aryl hydrocarbon receptor-interacting protein in

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Overview of pituitary adenomaPituitary adenomas are benign, monoclonal neoplasms of the anterior pituitary gland, accounting for approximately 10–15% of intracranial neoplasms [1,2]. A meta-ana lysis by Ezzat et al. in 2004 showed that pituitary adenomas occur with a frequency of 14.4% (range: 1–35%) and 22.5% (range: 1–40%) in pooled autopsy and radiological series, respectively [3]. This study indicated that cur-rent prevalence figures are significantly skewed by under-diagnosis of preclinical adenomas. A recent study on symptomatic pituitary adeno-mas in Liege, Belgium, provides an indication of the incidence of clinically apparent pitu-itary adenomas, showing a prevalence of one in 1064, a figure three- to five-times higher than earlier estimates [4]. This figure has been verified in a more recent study in Banbury, UK, which estimated a similar prevalence of one in 1288 individuals [5].

Two thirds of pituitary adenomas produce an excess of endogenous hormones, while a third are clinically nonfunctioning adenomas presenting owing to symptoms of local expansion and loss of endocrine function [6,7]. Pituitary adenomas are largely sporadic, with approximately 5% of pituitary adenomas being familial in origin [8]. Approximately 3% of pituitary adenomas arise due to mutations in the multiple endocrine neoplasia type 1 (MEN1) gene or owing to the Carney complex (CNC) [9,10]. The MEN1 gene is located on chromosome 11q13 and acts as a tumor-suppressor gene, encoding the nuclear protein menin [10]. Mutations typically result in a truncated menin protein. Approximately 40% of those possessing a mutated MEN1 gene develop pituitary adenomas [11], although almost all carrier subjects develop at least one feature of the disease by the age of 50 years [12,13]. More recently, a MEN1-like syndrome has been reported relating to mutations in the

Joshua W Cain1, Dragana Miljic2, Vera Popovic2 and Márta Korbonits†1

1Department of Endocrinology, Barts and the London School of Medicine, Queen Mary University of London, EC1M 6BQ, UK 2Institute of Endocrinology, School of Medicine, University Belgrade Belgrade, Serbia †Author for correspondence:Tel.: +44 207 882 6238 Fax: +44 207 882 6197 [email protected]

Pituitary adenomas are typically sporadic benign tumors. However, approximately 5% of cases have been found to be familial in origin. Of these, approximately 40% occur in the absence of multiple endocrine neoplasia type 1 or Carney complex and have been termed ‘familial isolated pituitary adenoma’ (FIPA). Recently, germline mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene have been described in 15–20% of these families, identifying an autosomal dominant condition with incomplete penetrance termed ‘pituitary adenoma predisposition’. Pituitary adenoma predisposition cohorts show a marked disposition to develop large, aggressive somatotroph, somatolactotroph or lactotroph adenomas, typically presenting at a young age. AIP mutation families have a distinct clinical phenotype compared with AIP mutation-negative FIPA families. Current evidence suggests that AIP is a tumor-suppressor gene. AIP has been demonstrated to interact with a number of cellular proteins, including several nuclear receptors, heat-shock protein 90 and survivin, although the mechanism of the tumor-suppressor effect is unknown. This article summarizes available data regarding the role of AIP in pituitary tumorigenesis and the clinical features of FIPA.

Keywords: AhR • AIP • aryl hydrocarbon receptor • aryl hydrocarbon receptor-interacting protein • familial isolated pituitary adenoma • FIPA • PAP • pituitary adenoma • pituitary adenoma predisposition • tumor-suppressor gene

Role of the aryl hydrocarbon receptor-interacting protein in familial isolated pituitary adenomaExpert Rev. Endocrinol. Metab. 5(5), 681–695 (2010)

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cyclin-dependent kinase inhibitor 1B (CDKN1B) gene at chro-mosome 12p13 [14]; however, this syndrome has only been found in five families to date [14–17]. CNC has a significantly lower prevalence than MEN1, with only 500 cases having been identi-fied to date [18]. Approximately 60% of CNCs arise owing to a mutation in the protein kinase A 1A regulatory subunit gene (PRKAR1A) located on chromosome 17q22–24 or owing to a currently unknown gene at the chromosome 2p16 locus [19].

Pituitary adenoma patients with an established family history of pituitary adenomas are classified as having familial isolated pituitary adenoma (FIPA) in the absence of features of either MEN1 or CNC syndrome [20,21]. In 1995, Benlian et al. estab-lished that there must be a novel genetic cause for low-penetrance familial pituitary adenomas in a study assessing a FIPA family with MEN1-negative somatotropinomas. The study concluded that there was a low-penetrance causative gene close to the MEN1 locus [22]. Frohman’s and Yamada’s research group, among others, has also observed a loss of heterozygosity (LOH) at the MEN1 locus, and similarly suggested that the causative gene is distinct from MEN1 [2,23–27]. Finally, in 2006, Vierimaa et al. identified the aryl hydrocarbon receptor-interacting protein (AIP) gene at chromosome 11q13, near the MEN1 locus, as being a causative gene in some FIPA patients, and suggested the term ‘pituitary adenoma predisposition’ (PAP) to describe patients harboring AIP mutations [28]. Further studies have indicated that the AIP gene is responsible for approximately 15–20% of families with pituitary adenomas observed in FIPA cohorts, and this figure rises to 40% if FIPA data are selected only for families with two or more members with somatotropinoma (termed isolated familial somato tropinoma [24]) [8,29]. The large proportion of AIP mutation-negative FIPA families suggests that there may be more causative genes associated with FIPA yet to be identified.

Identification of the AIP geneIn 2006, two families with pituitary adenomas in Northern Finland were selected for study by Vierimaa et al. [28]. Using high-stringency criteria (considering only those with acromegaly or gigantism), a genome-wide single-nucleotide polymorphism study on 16 patients was performed to identify the gene locus. Linkage ana lysis identified linkage at chromosome 11q12–11q13, which also includes the MEN1 gene locus; however, no MEN1 mutations were detected in the cohort. Further genotyping with 36 markers in both families revealed a logarithm of the odds score of 7.1 with high-stringency criteria at chromosome 11q13, with both families sharing the linked haplotype, segregating perfectly with acromegaly. This evidence supported previously published data indicating that this locus contained a gene responsible for familial acromegaly [2,22–27].

Expression profiling on leukocyte-derived RNA was performed and the linked region was mapped with 172 probe sets. Based on these data, two candidate genes were chosen for investigation, AIP and galectin-12 (LGALS12). The team found a nonsense mutation, p.Q14X, in exon 1 of the AIP gene that segregated with disease status (although two young female patients with prolac-tinoma turned out to be phenocopies because no AIP mutation

was identified). The p.Q14X mutation was absent in 209 local blood donor controls. Interestingly, genotyping of multiple AIP-carrier families in recent publications has shown this mutation to be unique to the two Finnish families, and a small number of Finnish sporadic pituitary adenoma patients, suggesting it to be a founder mutation [30,31].

To date, 49 variants have been identified throughout the AIP gene (Table 1 & Figure 1). These mutations have included deletions, insertions, segmental duplications, nonsense and missense muta-tions [24,26–28,31–52]. Splice-site and promoter mutations have also been described (Figure 2) [28,32,33]. The most commonly occurring mutations are at the p.R304 locus where both members of a CpG site have been found to be mutated, resulting in either a non-sense (c.910C>T, p.R304X) or a missense (c.911G>A, p.R304Q) mutation [31,33,37,51]. These mutations have now been reported in multiple unrelated families and in sporadic cases, indicating a potential mutational hot-spot [29,52]. Approximately 10% of families investigated by DNA sequencing will harbor larger AIP gene deletions [31,37,51]. This indicates that genetic identification in suspected families should not be limited to the sequencing of exons, intron junctions and promoter regions, but should include a technique such as the multiplex ligation-dependent probe ampli-fication (MLPA) technique, a technique specifically designed for identification of larger gene deletions that are frequently missed by conventional sequencing [37,51,53]. Some of the variants identi-fied and listed in Table 1 & Figure 1 may be rare polymorphisms and not disease-causing mutations. Data based on ana lysis of the general population, LOH and functional studies suggest that the p.R16H [32,36,38,48,54], p.V49M [35] and p.A299V [36,51] variants may be rare single-nucleotide polymorphisms.

Analysis of AIP status in family pedigrees has indicated that PAP is a heterozygous autosomal dominant disease with variable penetrance [55]. The observed LOH at the AIP locus in affected individuals suggests the role of AIP to be a tumor-suppressor gene, with loss of the wild type allele causing PAP in concordance with the Knudson’s two-hit hypothesis [15]. All known affected indi-viduals are heterozygous for the AIP mutation, with knock-out studies thus far determining homozygote mice being nonviable owing to fatal congenital cardiovascular abnormalities occurring during embryonic development [56]. Penetrance is suggested to be incomplete at approximately 30% [39,51]; however, this figure varies widely between families [8,33].

Characteristics of AIPAIP, also called the aryl hydrocarbon receptor-associated pro-tein 9 (ARA9) [57] was initially identified via interaction with the hepatitis B virus X protein [58] and termed the ‘immuno philin-like X-associated protein 2’ (XAP2) [59]. The AIP gene consists of six exons, coding a 330 amino acid, 37-kDa protein that exhibits FK506-binding protein 12 (FKBP12) homology in the amino ter-minus [60] and contains three protein–protein interaction-mediating tetratricopeptide repeats (TPR) and an a-helix in the C-terminal region (Figure 3) [61]. Despite the FKBP12 homology domain, AIP does not exhibit the properties of an immunophilin [60], while AIP displays properties of other TPR-domain peptides such as

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HOP, CHIP, Cyp40, FKBP51, FKBP52 and PP5, in terms of binding numerous partners including the heat-shock protein (Hsp) 90 [57].

AIP acts as a regulator of aryl hydro-carbon receptor (AhR) activity, mediating the response to xenobiotic compounds [59]. Formation of an AIP/AhR/Hsp90-dimer/p23 complex (Figure 4) results in sta-bilization of AhR within the cytoplasm, preventing unliganded nucleocytoplas-mic shuttling and protecting AhR from ubiquitin-proteasome pathway degrada-tion [62–64]. Structural ana lysis of AIP has demonstrated that the last five amino acids at the C-terminus are vital for association with AhR. Studies have shown that any mutation leading to a truncated protein, or disruption in the terminal five amino acids, results in failure to associate with AhR [59,61,65–67] and loss of function [33]. Studies have also shown that the third TPR domain is required in the binding of both Hsp90 and AhR [59,65,66]. Although it is not known if AhR is the relevant interacting factor for the tumorigenesis role of AIP, the two terminal TPR domains and the final a-helix are probably important to binding several, if not all, known partners of AIP. Therefore, it is not surprising that of the known AIP mutations, 71% cause disrup-tion to the C-terminus of the AIP protein (Figure 1).

AIP also interacts with a number of other compounds within the cell, including PPARa [68], the glucocorticoid receptor [69], translocase of the outer membrane of mito-chondria 20 (TOMM20) [70], b-thyroid receptor (THRb1) [71], survivin [72], phospho diesterase (PDE) 4A5 and 2A [73,74], RET, a proto-oncogene receptor tyrosine kinase [75], the subtype 13 a-subunit of the G protein family (Ga13

) [60], the Epstein-Barr

virus-encoded nuclear protein (EBNA-3) [76] and Hsc70, a Hsp70 family member [70], shown to preferentially bind AIP over Hsp90 in the absence of AhR [70,77].

The aryl hydrocarbon receptorAhR is a ligand-activated member of the basic helix-loop-helix/Per-Arnt-Sim (bHLH/PAS) family of transcription fac-tors [78] that forms a tetrameric complex with AIP, a 90-kD Hsp90 dimer [67] and the co-chaperone p23 (Figure 4) [79]. AhR

Table 1. Mutations identified within the aryl hydrocarbon receptor-interacting protein gene.

AIP mutation Mutation type Ref.

Transcript Protein level

c.40C>T p.Q14X Nonsense [28,36,46]

c.64C>T p.R22X Nonsense [31]

c.70G>T p.E24X Nonsense [24,33]

c.241C>T p.R81X Nonsense [26,33,49,50]

c.424C>T p.Q142X Nonsense [32]


c.601A>T p.K201X Nonsense [38]



c.721A>T p.K241X Nonsense [41]

c.804A>C p.Y268X Nonsense [43,44]

c.910C>T p.R304X Nonsense [28,32,33,38,40]

c.47G>A p.R16H Missense [32]

c.145G>A p.V49M Missense [35]

c.308A>G p.K103R Missense [41]

c.713G>A p.C238Y Missense [24,33]

c.721A>G p.K241E Missense [32]

c.769A>G p.I257V Missense [47]

c.811C>T p.R271W Missense [32,52]

c.896C>T p.A299V Missense [36]

c.911G>A p.R304Q Missense [33,36,38]

c.74_81delins7 p.L25PfsX130 fs [51]

c.286_287delGT p.V96PfsX32 fs [27,35]

p.P114fs fs [41]

c.404delA p.H135LfsX20 fs [38]

c.500delC p.P167HfsX3 fs [131]

c.517_521delGAAGA p.E174fsX47 fs [32,39]

c.542delT p.L181fsX13 fs [36]

c.662dupC p.E222X fs [51]

c.824_825insA p.H275QfsX12 fs [36]

c.854_857delAGGC p.Q285fsX16 fs [32]

c.919insC p.Q307RfsX103 fs [41]

Novel fs mutations in Ex2 fs [48]

c.100–1G>C IVS2–1G>C Splice site [36]

c.249G>T p.G83AfsX15 Splice site [51]

AIP: Aryl hydrocarbon receptor-interacting protein; del: Deletion; dup: Duplication; Ex2: Exon 2; fs: Frameshift; ins: Insertion.

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also interacts with the E3 ubiquitin ligase C-terminal of Hsp70 interacting protein (CHIP) [80], a more recently identified bind-ing partner believed to mediate ubiquitation of Hsp90 binding proteins [81], indicating a potential role in AhR regulation [82].

AhR mediates the cellular response to xenobiotic compounds such as dioxin, also known as 2,3,7,8-tetrachloro dibenzo-p-dioxin [57,58], and other hydrophobic environmental pollutants such as polycyclic aromatic hydrocarbons (PAH) – a group of over 200 compounds characterized structurally by the presence of two or more fused benzene rings [83]. PAHs are formed as a result of the incomplete combustion of fossil fuels [84–86] and have been found in cigarette smoke and charbroiled or smoked foods [87,88]. Dioxins and PAHs are known to exhibit mutagenic and carcino-genic effects [83]. AhR, when activated by PAH, is known to associate with RelB, driving the production of proinflammatory mediators such as IL-8 [89].

Prior to activation, dormant AhR is localized in the cytoplasm held in a stabilizing AhR/AIP/Hsp90/p23 complex; however, upon interaction with xenobiotic compounds, the cytoplasmic AhR/AIP/Hsp90 complex translocates to the nucleus where AhR undergoes a conformational change, detaching AhR from the protein complex [63,90–92]. The role of p23 in translo cation of AhR is yet to be identified. Within the nucleus, AhR forms a transcriptionally active dimeric complex with the AhR nuclear translator (ARNT), following which the AhR/ARNT complex

binds to DNA at the xenobiotic response element, also known as the dioxin response element, sites within the promoter region of target genes, inducing transcription of xenobiotic-metabolizing enzymes [60,93,94]. Gene targets include the cytochrome p450 (CYP) drug-metabolizing enzyme fam-ily (CYP1A1, CYP1A2 and CYP1B1), glutathionine-S-transferase, NADPH/quinine oxidoreductase and aldehyde dehydrogenase 3 [60,94,95].

However, there is evidence that AhR undergoes nucleocytoplasmic shuttling in the absence of exogenous xenobiotic compounds [64,96–98], with more recent studies suggesting that AhR undergoes nuclear translocation in the presence of cAMP [82,99]. This may be relevant because AIP has been shown to bind some phos-phodiesterases (PDEs) – a group of cAMP-degrading enzymes [73,74]. cAMP appears to interact with AhR as part of an endog-enous system that has been suggested to be important for the embryonic develop-ment of the liver and vascular system and maturation of the immune system [100–102].

Current data regarding the role of AIP in AhR regulation are conflicting, with some studies indicating that AIP increases AhR levels in the cytoplasm, increasing the tran-

scriptional activity of AhR [64,67], while other studies have shown that AIP has an inhibitory effect on AhR-induced transcription [62,103]. Additionally, there is also controversy regarding whether AhR itself is tumorigenic or inhibits cell proliferation. Numerous studies point to a tumorigenic effect [83,104–108], while others to a tumor-suppressor effect [108–111]. A unifying explanation to these controversial effects, although not compatible with all studies [108], was suggested by Peng et al. [112]. In the absence of ligand, AhR promotes cell cycle progression via binding cyclin-depen-dent kinase 4 [113], while AhR activation results in interactions with the retinoblastoma protein that lead to perturbation of the cell cycle, G0/G1 arrest, diminished capacity for DNA replica-tion and inhibition of cell proliferation. It is hypothesized [114] that AhR may function as a tumor-suppressor gene that becomes silenced in the process of tumor formation. AhR silencing may be associated with cancer progression, as shown in experiments using liver [112] or breast cell lines [115].

Role of AIP in tumorigenesisThe exact mechanism of tumorigenesis in the absence of AIP is not fully understood. Recent studies have indicated that AIP slows cell proliferation in pituitary cells when overexpressed [33] and a lack of AIP induces cell proliferation [116], reinforcing the idea of AIP being a tumor-suppressor gene, as previously hypoth-esized [24,28]. This provides an indication of the role of AIP in

Table 1. Mutations identified within the aryl hydrocarbon receptor-interacting protein gene (cont.).

AIP mutation Mutation type Ref.

Transcript Protein level

c.468 and 15C>T IVS3+15C>T Splice site [47]

c.469–2A>G IVS3–2A>G Splice site [38]

c.469–1G>A IVS3–1G>A Splice site [28]

c.807C>T p.F269= Splice site [33,34]

c.-270_269CG>AA and c.-220G>A

Promoter [33]

c.66_71delAGGAGA p.G23_E24del In-frame deletion [36]

c.138_161del24 p.G47_R54del In-frame deletion [32]

c.742_744delTAC p.Y248del In-frame deletion [45]

c.880_891delCTGGACCCAGCCandc.878_879AG>GT

p.L294_A297delandp.E293G

In-frame deletion [36]

c.805_825dup p.F269_H275dup In-frame insertion [26,33,137]

c.100–1025_279+357 (Ex2del) p.A34_K93 Large genomic del [37]

c.1104–109_279+578 (Ex1_Ex2del)

Large genomic del [37]

Whole gene del Large genomic del [51]

c.1-?_993+?del- Whole protein del Large genomic del [51]

AIP: Aryl hydrocarbon receptor-interacting protein; del: Deletion; dup: Duplication; Ex2: Exon 2; fs: Frameshift; ins: Insertion.


Review

Missense mutation In-frame deletion

In-frame insertion

C-teminus conserved protein:

C-terminus truncated protein: Nonsense mutation

Large deletions

Splice site

Promoter mutation

Frameshift mutation

Whole gene deletion

c.-270_269CG>AA and c.-220G>A

Novel frameshift p.P114fs p.Q142X c.1-?_993+?del- p. F269_H275dup

p.V96PfsX32

IVS3+15G>T p.E222X p.Q239X p.H275QfsX12

p.G23_E24del p.G83AfsX15 IVS3-1G>A p.K241Xp.L294_A297del

andp.E293G

p.G47_R54del p.Q217X

p.P167HfsX3

p.R304X

p.Q307fsX103p.L25PfsX130

p.E24X

p.R22X

p.R16H

p.Q14X

p.V49M

p.R81X

IVS2-1G>C

Ex2del

Ex1_Ex2del

p.K103R

IVS3-2A>G

p.H135LfsX20

p.K201X

p.C238Y

p.K241E

p.L181fsX13

p.E174fsX47

p.Q164X p.Y248del

p.I257V

p.R304Q

p.A299V

p.Q285fsX16

p.R271W

p.F269=

p.Y268X

Exon 2 Exon 3 Exon 4 Exon 5 Exon 6Exon 1

Role of the AIP gene in familial isolated pituitary adenoma

pituitary cell proliferation. This evidence suggests that loss-of-function mutations in the AIP gene may result in dysregulated cell proliferation that is likely to lead to neoplasia.

Studies regarding AIP–AhR interaction and the tumorigenic potential of AhR are often conflicting [117–119]. Several pathways have been suggested to be involved in AhR-related tumorigenesis, including those of JunD and cyclin A [105], E2F1 [120], p53 deg-radation [104] and the AhR repressor [106], as well as the telomere-independent senescence response [107]. A recent study by Park et al. produced evidence that AhR can cause DNA damage without the formation of an AhR/ARNT complex and without interaction with the xenobiotic response element region of DNA [83]. The study found that translocation of AhR when associated with PAHs can go on to directly damage DNA by concentrating the PAHs within the nucleus, leading to oxidative DNA strand breaks. The role of AhR in pituitary tumorigenesis is unclear, but it has been observed that AhR expression is reduced in AIP mutant pitui-tary adenomas [121]. The expression of ARNT is reduced in AIP mutation-positive adenomas compared with AIP-negative sporadic cases [116], while the expression of AhR repressor is increased in sporadic growth hormone (GH)-secreting tumors [122].

AIP is known to interact with the PDEs. There are more than 50 isoforms of PDE, and binding of AIP varies between differ-ent isoforms [73]. AIP is only known to bind to two PDE iso-forms, 4A5 and 2A [73,74], via the TPR region of the protein [74]. PDEs moderate cellular cAMP levels via hydrolysis of cAMP to AMP [73].

Phosphodiesterase 4A5 was the first PDE identified as a binding partner of AIP, binding via interaction with the TPR domains and reducing PDE4A5 function. Reduced function indirectly raises cAMP levels [73,123]. Given that AIP inhibits the enzymatic function of PDE4A5, this would suggest that loss of AIP function leads to reduced cAMP levels. Somatotroph cell cAMP levels are vital for regulating cell replication and hormone synthesis [124] and increased cAMP could result in hypertrophy and hyperplasia of the pituitary, which could lead to the development of pituitary neoplasia [125,126]. These data do not support the tumorigenic role of AIP in somatotroph cells via this pathway.

de Oliveira et al. identified PDE2A as a binding partner of AIP, associating with the TPR domains of AIP via a GAF-B domain present in the PDE2A structure [74]. They suggested

Figure 1. Representation of each known mutation identified to date within the aryl hydrocarbon receptor-interacting protein gene.


Review

Splice site

Nonsense

Large genomic deletion

In-frame insertion

In-framedeletion

FrameshiftPromoter

Missense

12.50%

25.00%

25.00%

18.75%

2.08%

2.08%

8.33%

8.33%


that the association of PDE2A with AIP results in PDE2A being brought into close proximity to cytoplasmic AhR proteins, local-ized within the AIP/AhR/Hsp90/p23 complex. The catalytic activity of PDE2A is not affected by association with AIP; there-fore, the complex reduces local cAMP levels, reducing cAMP interaction with AhR [74]. It has been recognized that cAMP can cause translocation of AhR into the nucleus, independent of exogenous compounds [99]; therefore, the local reduction in cAMP in the vicinity of AhR provides a possible mechanism of action for AIP as a tumor-suppressor gene [82].

Another protein found to be associated with AIP is sur-vivin. Survivin is a member of the inhibitor of apoptosis fam-ily of proteins that prevent apoptosis via association with and inactivation of caspases. This inactivation prevents caspase-driven apoptosis [72,127]. Survivin forms a complex with AIP and Hsp90 resulting in stabilization of survivin by preventing ubiquitination [72,128]. Knock-out studies have shown that the loss of AIP results in decreased survivin levels, resulting in apoptosis [72]. These data do not support the tumor-suppressor role of AIP in this context. However, another binding partner of AIP, RET, can change the AIP–survivin interaction [75]. RET has an interesting dual role – it produces survival signals in the presence of its ligand glial cell line-derived neurotropic factor. However, in the absence of glial cell line-derived neurotropic factor, it is proapoptopic. Activating RET mutations result in MEN2 or medullary thyroid carcinoma syndrome, while inactivating mutations cause Hirschprung disease. Binding of AIP to RET results in disassociation of AIP from survivin, resulting in increased ubiquitination of survivin, reducing cell

survival signals [75]. This proposed inter-action supports the hypothesis that AIP is a tumor-suppressor gene.

AIP has been found to be widely dis-tributed in the tissues of the body, hav-ing been isolated in tissues of the brain, colon, heart, kidney, leukocytes, liver, lung, ovary, pancreas, pituitary, pla-centa, prostate, skeletal muscle, small intestine, spleen, testes and thymus [33,58]. Considering that AIP is thought to be a tumor-suppressor gene, it could be expected that AIP mutation-positive patients are at an increased risk of devel-oping neoplastic changes in any tissue expressing AIP. Indeed, a few AIP muta-tion-positive families have been described by various types of other tumors [33], but these tumors are not uniform in their tis-sue of origin, and given the high preva-lence of tumors in general, not enough data are available to confirm the hypoth-esis. In terms of AIP mutations in other types of tumors, no somatic AIP muta-tions were identified in 373 patients with colorectal cancer, 82 patients with breast

cancer, 44 patients with prostate cancer [129] and 75 endocrine tumors (four paragangliomas, four pancreatic endocrine tumors, eight parathyroid, 26 thyroid, 19 adrenal, 16 neuroendocrine tumors and two mixed tumors) [46].

Comparison of the clinical characteristics of FIPA cohorts with & without AIP mutationsStudies into FIPA families have consistently found a dramatically different clinical picture in families harboring AIP mutations compared with both AIP mutation-negative FIPA families and those with sporadic pituitary adenoma.

Age at diagnosisThe mean age of diagnosis in our cohort of 64 families was found to be 33.2 ± 15.6 years, with AIP mutation-positive patients presenting 16.6 years earlier, on average, than those without AIP mutations (23.5 ± 11.0 years vs 39.8 ± 14.8 years; p < 0.0001).These data agree with the current literature, showing the mean age of diagnosis in those harboring AIP mutations to be, on average, 13–15 years earlier than in AIP mutation-negative patients [8,28,33].

The 2006 study by Daly et al. found that the age of diagnosis within FIPA families appears to decrease from one generation to another (50.5 ± 14.2 years vs 29.0 ± 16.3 years; p < 0.001) [20]. A similar trend can be observed in our cohort. We believe this phenomena is most probably not due to genetic anticipa-tion but to an increased awareness of symptoms due to the family history [8,20]. When selecting for families with more than one recorded generation, our data show that tumors in

Figure 2. A pie chart demonstrating the number and proportion of each known mutation type identified to date within the aryl hydrocarbon receptor interacting protein gene.


Review

N-terminus

C-terminusα-helix

TPR3

TPR2

TPR1

Role of the AIP gene in familial isolated pituitary adenoma

the second generation are diagnosed, on average, 17.7 years earlier than those in the first generation (41.3 ± 17.1 years vs 23.6 ± 10.4 years; p < 0.0001).

Pituitary tumor typesThe most common adenoma types in sporadic cohorts are prolac-tinomas (30–45%), somatotropinomas (20%), adrenocorticotro-pin hormone-secreting adenomas (10–12%), clinically nonfunc-tioning adenomas (20–25%), somatolactotropinomas, secreting both prolactin and GH (7%) and thyrotropinomas (1–2%) [1,6]. Within the unselected FIPA cohort of Beckers’ group, adenoma presentation is similar to that of the sporadic onset patients, with 41% presenting with prolactinomas, 30% somatotropinomas, 7% somatolactotropinomas and the remaining 23% compris-ing of adrenocorticotropin hormone-secreting adenomas, clini-cally nonfunctioning and thyrotropinomas [15]. Conversely, AIP mutation-positive families in this cohort exhibit 87.5% soma-totropinomas and 9.4% prolactinomas [130], with nonfunctioning and corticotropic pituitary adenomas being rare [8]. However, in our cohort of 64 FIPA families, we observed a predisposition to somatotropinomas, primarily in AIP mutation-positive patients but also in AIP-negative families (Table 2).

Gender differenceInterestingly, our data suggest that there is a gender difference in prevalence between pituitary adenomas in AIP mutation -positive and -negative FIPA families, with approximately two out of three (65.7%, 69 male vs 33 female; n = 105) AIP mutation-posi-tive patients being male, compared with 57.0% in unselected

FIPA patients (114 male vs 86 female) or 47.5% in AIP negative FIPA patients. While our data are supported by earlier reports regarding male predominance (71%) in AIP mutation posi-tive patients [130], we do not find female preponderance [15] in AIP-negative families.

Owing to the interesting link between gender and tumorigen-esis in AIP-positive families, we decided to look into the mode of inheritance in AIP mutation-positive families and unselected FIPA cohorts to determine if there was any difference in mater-nal and paternal transmission between the groups. We gathered inheritance information on 127 individuals, 82 of whom pos-sessed an AIP mutation. We determined that in unselected FIPA cases, maternal to paternal transmission was 52:75, respectively, indicating that transmission was 40.9% maternal and 59.1% paternal, whereas within AIP mutation-positive families, the maternal to paternal transmission was 27:55, respectively, giving a 32.9% maternal versus 67.1% paternal transmission, indicat-ing that both FIPA and PAP transmission via the father is more common. This trend may suggest a link to potential genomic imprinting, although if this were the case, transmission would likely be more skewed to paternal transmission. Another potential explanation for this may relate to a differing effect of pituitary adenomas on fertility in males and females. We believe that dis-rupted pituitary function results in abnormal luteinizing hor-mone/follicle-stimulating hormone regulation, which will lead to loss of ovulation in females. However, in males, reduction of luteinizing hormone and follicle-stimulating hormone might result in lower testosterone levels without complete loss of sperma-togenesis; therefore, some level of fertility is maintained. Because AIP mutation-positive patients are affected at a younger age, this effect would be more pronounced in this population.

PenetranceOur data were analyzed to determine whether there is a dif-ference in penetrance between AIP mutation-positive and -negative FIPA cohorts. Our 44 AIP mutation-negative families contained 96 affected individuals and a calculated number of carriers of 293, giving an estimated penetrance of 32.7%. Our ana lysis of the 20 AIP mutation-positive families, containing 66 affected individuals and 200 carriers, demonstrated a simi-lar penetrance of 33.0%. While this figure agrees with current

Figure 3. The three tetratricopeptide repeats regions of the aryl hydrocarbon recptor-interacting protein and the terminal α-helix.TPR: Tetratricopeptide repeats.

p23 Hsp90 dimer AIP AhR

Figure 4. The AIP/AhR/Hsp90/p23 complex.AhR: Aryl hydrocarbon receptor; AIP: Aryl hydrocarbon receptor-interacting protein; Hsp: Heat-shock protein.


Review

210 cmat age of 21 years

175 cmat age of 10 years


estimates placing the penetrance in AIP mutation-positive fami-lies between 15–30% [39,51], it does not indicate a significant difference in penetrance between AIP mutation-negative and -positive families with FIPA. However, approaching the same questions in an alternative way, there is a noted difference in the number of individuals with disease in FIPA families with and without AIP mutations [51]. Analysis of 64 families, 20 AIP mutation-positive and 44 AIP mutation-negative, has shown that AIP-positive families have, on average, 3.2 ± 1.8 compared with 2.2 ± 0.5 members (p = 0.0006) in AIP mutation-negative fami-lies. This appears to indicate a difference in penetrance between AIP mutation-positive and -negative FIPA cohorts. However, we need to be aware that while AIP mutations often cause early-onset GH-secreting adenomas making the clinical diagnosis relatively straight forward, the more variable tumor type and later onset in AIP mutation-negative families could confound recognition of the disease and therefore penetrance calculations.

The factors influencing penetrance are dif-ficult to determine and the possibility of a second locus has been suggested, although not confirmed [131].

We also looked into the penetrance for specific mutation types within AIP muta-tion-positive families. A total of 16 out of 20 of our AIP mutation-positive fami-lies posessed a truncating mutation, with 56 affected individuals and 177 carriers, giving a penetrance of 32.7%. Interestingly, our four AIP mutation-positive families with nontruncating mutations included

ten affected individuals and 23 carriers, giving a penetrance of 43.5%. We believe that the number of families available for these calculations excludes the possibility to provide reliable estimates here, but does suggest an interesting point for further investiga-tion witha larger sample size.

The AIP-positive patients typically develop aggressive soma-totroph macroadenomas [32,33,130]. AIP-positive patients also typically have a young age at diagnosis (<25–30 years) [15], whereas with sporadic pituitary adenomas, occurrence in the young is rare. In our cohort, 32 patients presented younger than 18 years – of these, 78.1% (n = 25) were AIP mutation positive. The predisposition to develop adenomas at a young age results in 80% (16 out of 20) of families harboring AIP mutations experiencing childhood-onset adenoma, while only 11.4% (5 out of 44) of AIP mutation-negative FIPA families have a childhood-onset case. It is therefore important to con-sider an AIP mutation in all patients with early-onset pituitary

adenoma or gigantism. A large number of families recruited into our cohort were initially identified via early-onset disease (Figure 5). We believe that through wide-spread awareness of the high prevalence of AIP mutation in early-onset pituitary ade-noma, more families would be investigated for potential mutations, allowing better management of other carriers who are at risk of developing disease.

The term ‘acromegaly’ was first used by Pierre Marie in 1886, describing a condi-tion characterized by hypertrophy of the hands, feet and face, although many other physicians had previously described the same condition [132,133]. Initially, acromeg-aly and gigantism were considered separate clinical entities; later, gigantism was con-sidered a congenital disease and acromegaly an acquired disease [134]. With the increas-ing recognition of AIP mutations in famil-ial and sporadic giants, the original idea that gigantism can be a result of a genetic predisposition is, in some cases, not too far from the truth.

Table 2. Pituitary adenoma types in our cohort of 64 families.

Adenoma type All FIPA (%) AIP mutation-positive (%)

AIP mutation-negative (%)

Somatotropinoma 65 (n = 104) 76.6 (n = 49) 57.3 (n = 55)

Lactotroph adenoma 19.4 (n = 31) 10.9 (n = 7) 25.0 (n = 24)

Somatolactotropinoma 4.4 (n = 7) 7.8 (n = 5) 2.1 (n = 2)

Clinically nonfunctioning pituitary adenoma

10.6 (n = 17) 4.7 (n = 3) 14.6 (n = 14)

Corticotropinoma 0.6 (n = 1) 0.0 (n = 0) 1.0 9 (n = 1)

AIP: Aryl hydrocarbon receptor-interacting protein; FIPA: Familial isolated pituitary adenoma.

Figure 5. Family tree and photograph of two aryl hydrocarbon receptor-interacting protein mutation positive siblings with gigantism. The female patient was diagnosed with a growth hormone-secreting macroadenoma at the age of 10 years (175 cm, >>99 percentile), was treated with two surgeries and radiotherapy and currently is cured of acromegaly and on full pituitary hormone replacement. Her brother was diagnosed age 21 years (210 cm) with a growth hormone-secreting macroadenoma, and after surgery and radiotherapy, he has residual disease with poor response to somatostatin analogs.



Prevalence of AIP mutations identified in sporadic patientsRecent cohort studies agree that AIP muta-tions can be identified in approximately 3–4% of unselected sporadic pituitary adenoma cases [36,38]. These mutations are germline mutations and no somatic muta-tions have been found in pituitary adeno-mas to date [31,33,75]. Evidence suggests that presentation of seemingly sporadic AIP mutation-positive pituitary adenoma is simi-lar to that in the familial setting. Patients typically present at a young age (majority are <25 years), most commonly with somatotro-pinoma. Therefore, it is important to con-sider an AIP mutation in all sporadic patients presenting early with somatotropinoma. However, in our experience [33], the major-ity of childhood-onset sporadic acromegaly cases do not carry AIP mutations, such as the patient shown in Figure 6.

We analyzed all the AIP mutation-positive sporadic patients published in the literature to date, together with two AIP mutation-positive sporadic patients from our cohort (Table 3) [Korbonits M, Unpublished

Data]. Analysis of the data reveals a mean age of diagnosis of 24.4 ± 9.2 years, with 59.3% of patients being male (16 out of 27) and 40.7% of patients being female (11 out of 27). Of the AIP mutation-positive spo-radic patients, 75% (21 out of 28) of the group possessed somatotropinomas. These trends fit with those observed in FIPA cohorts harboring an AIP mutation, sug-gesting that the presentation of AIP muta-tion-positive patients is similar in both the familial and sporadic settings.

Interestingly, eight of the 28 patients pos-sessed the p.Q14X mutation, all of which originated in Finland, suggesting that these cases could be part of the founder mutation cohort identified in that region.

Role of immunohistochemistry in identification of AIP mutation-positive tumor tissuesAIP is preferentially expressed in somatotrophs and lactotrophs. This corresponds with the observation that AIP mutation-positive patients preferentially develop somatotropinomas and lactotropi-nomas. Currently, suspected AIP mutation-positive patients are diagnosed via conventional sequencing and MLPA. The potential role of immunohistochemistry in detection of reduced or absent AIP expression in excised pituitary adenomas has been studied and found not to be a reliable tool to predict the presence of AIP mutations [33,36,121]. In somatotroph adenomas where AIP staining

is not detected, an AIP mutation is likely, but positive AIP stain-ing does not rule out AIP mutations. This suggests that there is probably little role for immunohistochemistry in screening and the identification of AIP-mutant patients.

Clinical management of PAP familiesStudies regarding MEN1 have indicated that changes in the levels of IGF-1 and prolactin can be detected up to 10 years before a pitui-tary adenoma becomes clinically apparent [135]. Additionally, MRI scanning can often identify small adenomas before overt clinical

Table 3. AIP mutation-positive sporadic patients identified in the literature to date.

Gender Condition Age (years)

Mutation Ref.

Female Acromegaly 24 p.Q14X [1]

Male Acromegaly 42 p.Q14X [1]

Female Acromegaly 26 IVS3–1G>A [1]



Male Acromegaly 36 p.Q14X [2]


Male Acromegaly 20 IVS2–1G>C [2]

Male Gigantism 8 p.H275QfsX12 [2]

Unknown Cushing’s syndrome 26 p.R304Q [2]

Female Somatotropinoma 16 p.R304X [2]

Male Gigantism 28 p.V49M [35]

Male Acromegaly 24 p.R22X [4]

Male Gigantism 15 p.H135LfsX20 [12]

Male Acromegaly 40 IVS3–2A>G [12]

Female Acromegaly 27 p.K201X [12]

Male Acromegaly 24 p.K201X [12]

Female Acromegaly 37 p.R304Q [12]

Male Gigantism 17 p.R304X [12]

Male Prolactinoma 35 p.Q14X [3]

Female Somatolactotropinoma 35 p.Q14X [3]

Male Gigantism 19 p.Y248del [27]

Female Acromegaly 19 IVS3+15C>T [47]

Male Gigantism 15 fs in exon 2 [48]

Male Acromegaly 20 p.G23_E24del [2]

Male Acromegaly 18 p.L181fsX13 [2]

Male Gigantism 15 p.R271W [Korbonits M, Unpublished Data]

Female Gigantism 15 p.R304X [Korbonits M, Unpublished Data]

del: Deletion; fs: frameshift.



symptoms occur. If preclinical changes in blood bio chemistry were to be observed in AIP mutation-positive families this would allow early identification of pituitary adenomas in identified AIP mutation-positive families, via regular blood investigations. We suggest that patients with an AIP mutation should undergo base-line MRI and yearly screening for abnormal pituitary function, as is currently indicated in MEN1-positive patients [136].

The management of PAP families is a challenging task. Patients usually have large invasive adenomas and are often not responsive to somatostatin analogs [33]. Long-term follow-up of patients and asymptomatic carriers is vital for early prevention of disease. AIP mutation screening should be considered for all familial pituitary adenoma cases where MEN1 and CNC is unlikely and the genetic screening should involve both DNA sequencing and MLPA. This service is now available from an accredited NHS Laboratory in the UK. Owing to the young age of onset of pituitary adenoma in AIP mutation-positive families, predictive genetic testing of the children of the affected or carrier members should be considered at an early age, and based on the youngest known manifested case with AIP

mutation, screening by the age of 4 years could be considered. Identified carriers should undergo yearly clinical and biochemical assessments for abnormal pituitary function.

Expert commentaryFamilial isolated pituitary adenomas are increasingly recognized and awareness needs to be raised to their existence in addition to the classical MEN1 and CNC syndromes. A total of 15–20% of FIPA families harbor a mutation in the AIP gene. It is not known how AIP, a molecular co-chaperone, affects pituitary tumorigenesis, but over expression reduces, while inhibition increases cell pro-liferation in experimental settings. Thorough genetic ana lysis, including tests for large gene deletions, and possible assessment of functional status of a sequence change, helps to appropriately classify families.

Phenotypically, AIP mutation-positive and -negative families are quite distinct as a group, although individual families need to be studied carefully. The disease has a low penetrance, raising issues about clinical screening and genetic counseling.

Five-year viewAnalyzing and reporting families with FIPA will raise awareness of the possibility of a familial link in patients with pituitary ade-noma. Physicians will be able to refer these families to specialists early, allowing screening, early diagnosis and better management of a condition, which, if left untreated, could lead to considerable morbidity. Identification of the mechanism of how AIP is involved in pituitary tumorigenesis will help to design novel strategies to fight the disease. We envisage that other genes will be identified in the next few years that are responsible for the AIP mutation-negative cases in FIPA cohorts. We hope that advancements will also allow understanding of the causes of the incomplete pen-etrance observed in FIPA cohorts to the benefit of counseling carrier subjects.

Figure 6. Patient (17 years of age, 190 cm) with growth hormone-secreting macroadenoma. Following two pituitary surgeries and stereotactic radiotherapy, the patient is on somatostatin analog therapy. No family history of pituitary adenomas and no AIP mutation have been identified.

Key issues

• Pituitary adenomas have a prevalence of approximately one in 1100, 2% of which are classified as familial isolated pituitary adenoma (FIPA). Patients with a family history of isolated pituitary adenomas most often have growth hormone- or prolactin-secreting adenomas.

• A total of 15–20% of FIPA cases harbor an autosomal dominant mutation in the aryl hydrocarbon receptor-interacting protein (AIP) gene causing pituitary disease with incomplete penetrance (approximately 30%).

• AIP mutation-positive patients have distinct clinical characteristics. They present, on average, 16 years younger than AIP-negative FIPA patients, and have a predisposition to developing somatotropinoma, often leading to gigantism. These tumors tend to respond poorly to somatostatin analogs.

• Occasionally, seemingly sporadic pituitary patients are also found to harbor AIP mutations. The characteristic clinical features of AIP mutation-positive patients appear to be conserved through the sporadic and familial settings and allow a key indication of potential AIP mutation carriers.

• AIP is thought to be a tumor-suppressor gene, with loss of the normal allele resulting in tumor formation. It is unclear how AIP exerts its tumor-suppressor function. The roles of several interacting partners have been considered.

• Currently, research is ongoing to identify the gene or genes causing AIP mutation-negative FIPA.

• It is important to raise the awareness of the possible familial nature of pituitary tumors.



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Financial & competing interests disclosureJoshua W Cain was supported by the Wolfson foundation and the Association of Physicians of Great Britain and Ireland. Our laboratories’ FIPA project is supported by the Cancer Research Committee of St Bartholomew’s Hospital (London, UK). The FIPA project in Serbia was supported by a grant from

the Ministry of Science (145019). The authors have no other relevant affili-ations or financial involvement with any organization or entity with a finan-cial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.



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