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Mutations in the Aryl Hydrocarbon Receptor Interacting Protein Gene Are Not Highly Prevalent among Subjects with Sporadic Pituitary Adenomas

Department of Endocrinology (T.B., A.Ba.), Centre Hospitalier Universitaire Timone, and Laboratory of Biochemistry and Molecular Biology (M.S., A.E., A.Ba.), Centre Hospitalier Universitaire Conception, 13385 Marseille Cedex 5, France; Laboratoire Interactions Cellulaires Neuroendocriniennes (A.E., T.B., A.Ba.), Centre National de la Recherche Scientifique Unité Mixte de Recherche 6544, Institut Fédératif Jean Roche, Faculté de Médecine, Université de la Méditerranée, 13916 Marseille Cedex 20, France; Departments of Molecular Genetics (J.-F.V., V.B.) and Endocrinology (A.F.D., G.T., A.Be.), Centre Hospitalier Universitaire de Liège, University of Liège, 4000 Liège, Belgium; Department of Experimental Medicine (M.-L.J.-R.), University of L’Aquila and Neuromed, Istituto di Ricovero e Cura a Carattere Scientifico, 86077 Pozzili, Italy; Laboratory of Histology and Molecular Embryology (J.T.), Institut National de la Santé et de la Recherche Médicale U433, Faculty of Medicine Lyon-RTH Laennec, 69372 Lyon Cedex 08, France; and Service d’Endocrinologie (L.C.), Hôpital Cochin et Institut National de la Santé et de la Recherche Médicale U567, 75014 Paris, France

Address all correspondence and requests for reprints to: Professor Albert Beckers, M.D., Ph.D., Department of Endocrinology, Centre Hospitalier Universitaire de Liège, University of Liège, Domaine Universitaire du Sart Tilman, 4000 Liège, Belgium. E-mail: albert.beckers{at}chu.ulg.ac.be.

	Abstract

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Context: Limited screening suggests that three germline mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene are not involved in sporadic pituitary tumorigenesis. Multiple novel mutations of this gene have since been identified in familial isolated pituitary adenoma cohorts.

Objective: The objective of the study was to undertake full AIP coding sequence screening to assess for the presence of germline and somatic mutations in European Union subjects with sporadic pituitary tumors.

Design: The study design was the analysis of DNA from peripheral blood lymphocytes and analysis of exons 1–6 and paraexonic intron sequences of AIP. Multiplex ligation-dependent probe amplification was used to screen separate sporadic pituitary tumor tissue samples for discrete and extensive deletions or mutations of the AIP gene.

Setting: The study was conducted in university tertiary referral Clinical Genetics, Molecular Biology, and Endocrinology Departments.

Results: In 107 patients [prolactinomas (n =49), nonfunctioning tumors (n = 29), somatotropinomas (n = 26), ACTH-secreting tumors (n = 2), TSH-secreting tumors (n = 1)], no germline mutations of AIP were demonstrated. Among a group of 41 tumor samples from other subjects, a novel AIP mutation (R22X) was found in one sample in which the corresponding allele was deleted; follow-up screening of the patient demonstrated a germline R22X AIP mutation.

Conclusions: AIP mutations do not appear to play a prominent role in sporadic pituitary tumorigenesis in this population of European subjects.

	Introduction

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MOLECULAR GENETIC STUDY of pituitary tumors has identified a variety of mutations or abnormal expression pattern that may play a role in tumorigenesis. Well-recognized examples include mutations in the Gs gene, PTTG overexpression, and decreased MEG3 expression (1, 2, 3, 4). MEN1 and PRKAR1A gene mutations play a critical role in endocrine tumorigenesis in multiple endocrine neoplasia-1 (MEN1) and Carney complex (CNC) (5, 6) but are of limited significance in sporadic pituitary tumors (7, 8). Thus, interest remains high in the identification of new molecular mechanisms to explain sporadic adenoma formation (9).

Aryl hydrocarbon receptor interacting protein (AIP), a 330-amino-acid protein present in the pituitary, interacts with the aryl hydrocarbon receptor and heat shock protein 90 dimer; AIP is involved in mediating cellular responses to environmental toxins like dioxin (10, 11). Mutations that remove conserved tetratricopeptide repeat domains at the carboxy terminal of AIP abrogate proper interaction with its receptor and heat shock protein 90, thereby disrupting nuclear localization (11). Vierimaa et al. (12) first reported the involvement of three AIP mutations in pituitary adenomas in non-MEN1, non-CNC families from Finland and Italy. Among the Finnish cohort, two AIP mutations were noted in germline and somatic DNA from sporadic pituitary adenoma patients (12). Recently Daly et al. (13, 14) described the clinical and genetic features of families exhibiting familial isolated pituitary adenomas (FIPAs). Among 73 FIPA families, 10 AIP mutations were present among 11 families; nine of these mutations were novel (13). Yu et al. (15) demonstrated that the three germline mutations described by Vierimaa et al. were not prevalent among U.S. patients with sporadic pituitary adenomas. We undertook a study of 107 subjects with sporadic pituitary adenomas and 41 separate sporadic pituitary tumor samples to screen for germline and somatic mutations in the full coding sequence of AIP.

	Subjects and Methods

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Subjects

The study was performed in 107 patients with sporadic pituitary adenomas from university hospital centers in France (Marseilles), Belgium (Liège), and Italy (L’Aquila). There were 49 subjects with prolactinomas [17 males, 32 females; mean (±SD) age at diagnosis: 33.9 ± 13.0 yr; 70.2% macroadenomas, 52.5% cavernous sinus invasion], 26 with somatotropinomas [17 males, nine females, mean (±SD) age at diagnosis: 44.4 ± 13.3 yr; 86.4% macroadenomas, 45.0% cavernous sinus invasion], 29 with nonfunctioning pituitary adenomas [NFPAs; 15 males, 14 females; mean (±SD) age at diagnosis: 50.6 ± 13.1 yr; 100% macroadenomas, 58.8% cavernous sinus invasion], two females with noninvasive ACTH-secreting microadenomas [mean (±SD) age at diagnosis: 32.5 ± 4.9 yr], and one male subject with a noninvasive TSH-secreting microadenoma diagnosed at age 48 yr.

None of the subjects had a history of MEN1, CNC, or FIPA. Twelve subjects (11.2%) had other endocrine tumors: parathyroid adenoma (n = 10), pancreatic endocrine tumor (n = 1), and thymoma (n = 1); MEN1 gene mutations were outruled by gene sequencing. All subjects gave their written informed consent to participate in the study, which was approved by the local ethics committee.

Pituitary tumor samples

Forty-one frozen tissue samples from patients with sporadic pituitary tumors (different from the patients above) were collected as previously described (16) and studied for AIP gene mutations. These tumors, classified by immunohistochemical staining for pituitary hormones, included 23 somatotropinomas [13 males, 10 females; mean (±SD) age at diagnosis: 42 ± 13.9 yr] and 18 gonadotropinomas [nine males, nine females; mean (±SD) age at diagnosis: 45 ± 13.7 yr] and were clear of residual normal pituitary tissue before genetic analysis. Gs sequence was performed in all somatotropinoma samples, as described previously (16); seven tumors had point mutations in Gs, indicating the presence of the gsp oncogene.

Genomic analysis of AIP and MEN1

Using DNA isolated from peripheral blood, exons of the AIP and MEN1 genes were amplified using exon flanking primers (12, 17). Apart from exons 4 and 5 of AIP, the same primers were used for gene sequencing using a CEQ 8000 sequencer (Beckman Coulter, Fullerton, CA). The primers for AIP exons 4 and 5 were: GACGCAGCTGTGGTGTCC (AIP4F) and CTGAGGGGGAGGATGGAT (AIP5F). The primers used for sequencing AIP exons 1, 2, 3, and 6 and the MEN1 gene are available on request.

AIP single-nucleotide polymorphism patterns were studied using a reference population of 86 normal individuals from Belgium (n = 31), France (n = 25), and Italy (n = 30). In addition, an international panel of reference populations were analyzed as follows: exons 2 and 5 [Applera Genomics Initiative (AGI) Caucasian and African American samples, Coriell Cell Repositories], exon 4 (CEU; Utah residents of northern/western European ancestry), and exon 6 [Centre d’Etude du Polymorphisme Humain (CEPH)].

Multiplex ligation-dependent probe amplification (MLPA) analysis

Loss of heterozygosity (LOH) within the AIP gene and along larger segments of chromosome 11q was assessed in tumor samples using MLPA. MLPA probe design has been described previously (18). Control probe-pairs that were specific to unrelated genes on chromosomes 7 and 17 were also designed. All probes had amplification products from 87 to 136 bp in length and had an annealing temperature higher than 70 C as per the RAW Probe program (MRC-Holland, Amsterdam, The Netherlands). PCR products were analyzed on an ABI3100 capillary electrophoresis apparatus (Applied Biosystems, Lennik, Belgium). Copy number quantification involved normalization of the peak area of the AIP-specific MLPA probe by dividing it by the combined areas of the control probes. This ratio was compared with the similar ratio obtained from control DNA. LOH was observed when the wild-type signal was reduced by 35–60% for each AIP-specific probe.

	Results

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AIP analysis in genomic DNA

Analysis of the coding sequence of AIP in genomic DNA from 107 subjects with sporadic pituitary adenomas revealed no mutations. The genotype frequencies of polymorphisms were similar to those of the reference populations (Table 1).

MLPA analysis revealed deletions at the AIP locus in two of 41 frozen pituitary tumor fragments [somatotropinoma (n = 2)]. In one somatotropinoma, a nonsense mutation p.Arg22X (CGA>TGA) at exon 1 of AIP was found, indicating a hemizygotic state with the loss of wild-type allele (GenBank accession no. EF158450). This male subject presented with acromegaly at a young age (24 yr) due to a macroadenoma that secreted high levels of GH and was resistant to somatostatin agonist therapy. Radiotherapy was required 1 yr postoperatively due to activity of the residual tumor. Analysis of peripheral blood DNA in the patient also revealed a germline p.Arg22X mutation. There was no family history of pituitary adenomas in this case. The other somatotropinoma sample with a large deletion that included the AIP and MEN1 loci came from a young male with an invasive tumor. However, the corresponding AIP or MEN1 genes were intact in the other allele.

The genotype frequencies of all AIP polymorphisms were similar to those of the reference populations (Table 1).

	Discussion

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The involvement of AIP mutations in pituitary tumorigenesis was first suggested by Vierimaa et al. (12), who described three mutations (Q14X, R304X, and IVS3–1G>A) in subjects with somatotropinomas and prolactinomas. Daly et al. (13) recently described a further nine AIP mutations (R16H, G47_R54del, Q142X, E174 frameshift, Q217X, Q239X, K241E, R271W, and Q285 frameshift) in a cohort of 73 families with FIPA. Among these 12 described mutations, the majority lead to early stop codons and protein truncation, which would remove the third tetratricopeptide repeat domain and the last five carboxy-terminal amino acids that are necessary for the biological activity of AIP (10). Q14X and IVS3–1G>A occurred in Finnish individuals with sporadic pituitary tumors; LOH at the AIP locus was shown in all tumor samples analyzed. Subsequently Yu et al. (15) analyzed genomic DNA from 66 individuals with sporadic pituitary adenomas treated in a single tertiary referral center in the United States; they looked exclusively for the three mutations described previously by Vierimaa et al. (16). Because none of the patients had any of these three AIP mutations, the authors concluded that AIP was unlikely to be involved in the pathogenesis of sporadic pituitary tumors in a predominantly Californian group.

The results of the current study confirm the findings of Yu et al. (15) and expand our understanding of this issue in a number of ways. We undertook sequencing of the entire coding sequence of AIP. In that way we can conclude with certainty that AIP mutations did not play an important role in the pathogenesis of sporadic pituitary adenomas in our cohort. In the U.S. cohort, three of the 66 individuals (4.5%) had a family history of pituitary adenomas (two subjects with prolactinomas and one with a NFPA). These patients, negative for MEN1, may have comprised FIPA families. In FIPA, AIP mutations occur in about 15% of families, and tumors in such families can include somatotropinomas, mixed GH/prolactin-secreting tumors, prolactinomas, and NFPA (13). The majority of FIPA families, including 50% of those with familial somatotropinomas, are, however, negative for AIP mutations, indicating that other unidentified pathogenic factors may be involved. We also chose to screen DNA from subjects from three separate countries (France, Belgium, and Italy); absence of AIP mutations in genomic DNA from this geographically dispersed group supports the contention that founder effects may be involved in the frequent occurrence of the Q14X mutation in the Finnish cohort (12, 15).

Mutations in AIP are not, however, altogether absent among patients with sporadic pituitary adenomas. Our screening of tumor tissue revealed a p.Arg22X mutation in one AIP allele and a deletion of the other allele. Subsequently a germline AIP was also demonstrated in the same patient. The clinical characteristics (young age, large/aggressive tumor) of the patient are similar to those of other patients with AIP mutations recently described (13). This patient had no family history of pituitary adenomas or other endocrine disease. A tumor sample from another patient with a somatotropinoma had a deletion that also included both AIP and MEN1, but both genes in the other allele were wild type. This raises the possibility that a mutation in another gene in this region of 11q13 could be involved in pituitary tumorigenesis in such patients.

This study confirms that germline mutations of AIP are infrequently found in patients with sporadic pituitary adenomas in continental Europe. Founder effects should be considered when extrapolating from AIP mutation prevalence among genetically delimited populations. Given that at least 13 AIP mutations have been described in association with pituitary adenomas, full AIP sequencing is needed to outrule AIP involvement in sporadic pituitary tumorigenesis among other populations worldwide.

	Acknowledgments

 
We thank Nicole Peyrol and Sandrine Bosc (Laboratoire de Biochimie Biologie Moléculaire, Conception AP-HM) for their assistance in DNA sequencing and Dr. Rachel Desailloud [Centre Hospitalier Universitaire (CHU) Amiens], Dr. Emmanuel Sonnet (CHU Brest), Dr. Chantal Mounier (CHU St. Etienne), Dr. Anne Marie Guedj (CHU Nimes), Dr. Isabelle Morange (CHU Timone, Marseille), and Professor Olivier Chabre (CHU Grenoble) for identifying patients for the French arm of the study.

	Footnotes

 
This work was supported in part by the Oncogenic Network of the French Ministry of Health, Centre National de la Recherche Scientifique, University of Meditérranée, and Assistance Publique des Hôpitaux de Marseille.

A.Ba., J.-F.V, A.F.D., M.S., M.-L.J.-R., J.T., G.T., L.C., V.B., T.B., A.E., and A.Be. have nothing to declare.

First Published Online February 13, 2007

¹ A.Ba. and J.-F.V. contributed equally to this study.

Abbreviations: AGI, Applera Genomics Initiative; AIP, aryl hydrocarbon receptor interacting protein; CEPH, Centre d’Etude du Polymorphisme Humain; CNC, Carney complex; FIPA, familial isolated pituitary adenoma; LOH, loss of heterozygosity; MEN1, multiple endocrine neoplasia type 1; MLPA, multiplex ligation-dependent probe amplification; NFPA, nonfunctioning pituitary adenoma.

Received December 7, 2006.

Accepted February 5, 2007.

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This Article Abstract Full Text (PDF) All Versions of this Article: 92/5/1952    most recent Author Manuscript (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Barlier, A. Articles by Beckers, A. Search for Related Content PubMed PubMed Citation Articles by Barlier, A. Articles by Beckers, A. Related Collections Neuroendocrinology and Pituitary Endocrine Oncology