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Large Genomic Deletions in AIP in Pituitary Adenoma Predisposition

Department of Medical Genetics (M.G., E.H., A.K., L.A.A.), 00014 University of Helsinki, Helsinki, Finland; Medical Department III (R.P.), Leipzig University, 04103 Leipzig, Germany; Clinical Genetics (A.V.K.K.), Great Ormond Street National Health Service Trust, London WC1N 3JH, United Kingdom; Departments of Human Genetics, Oncology, and Medicine (M.T.), McGill University, Sir Mortimer B. Davis Jewish General Hospital, H3T 1E2 Montreal, Quebec, Canada; Departments of Clinical Genetics (O.V.) and Internal Medicine (P.S.), Oulu University Hospital, 90029 Oulu, Finland; Department of Endocrinology (T.S.), Helsinki University Central Hospital, 00029 Helsinki, Finland; Department of Internal Medicine (E.D.M.), General Hospital, 31044 Montebelluna, Italy; Department of Medicine and Pharmacology (S.C.), Section of Endocrinology, University of Messina, 98125 Messina, Italy; Division of Endocrinology-Metabolism and Diabetes (S.G.), Cerrahpaçsa Medical Faculty, University of Istanbul, 34303 Istanbul, Turkey; Wessex Clinical Genetics Service (A.L.), Princess Anne Hospital, SO16 5YA Southampton, United Kingdom; Department of Clinical Genetics (L.I.), New Guy’s House, Guy’s Hospital, London SE1 9RT, United Kingdom; Department of Medicine (S.A.), King’s College Hospital, Denmark Hill, London SE5 9RS, United Kingdom; Department of Endocrinology and Diabetes (G.B.), Thomas Addison Unit, London SW17 0QT, United Kingdom; Department of Clinical Genetics (S.H.), St. Georges, University of London, London SW17 ORE, United Kingdom; and Division of Endocrinology (C.A.K.), University of Mississippi Medical Center, Jackson, Mississippi 39216

Address all correspondence and requests for reprints to: Professor Lauri A. Aaltonen, Department of Medical Genetics, Biomedicum Helsinki, P.O. Box 63 (Haartmaninkatu 8), University of Helsinki, 00014 Helsinki, Finland. E-mail: lauri.aaltonen{at}helsinki.fi.

	Abstract

Top Abstract Introduction Subjects and Methods Results and Discussion References

 
Context: Germline mutations in AIP have been recently shown to cause pituitary adenoma predisposition (PAP). Subsequently, many intragenic germline mutations have been reported, both in familial and in sporadic settings.

Objective: Our objective was to evaluate the possible contribution of large genomic germline AIP deletions, an important mutation type in tumor predisposition syndromes, in PAP.

Design: Here, we applied the multiplex ligation-dependent probe amplification assay to examine whether large genomic AIP or MEN1 alterations account for a subset of PAP cases.

Patients: The study was performed on familial and sporadic pituitary adenoma cases of European origin, which had previously tested negative for germline AIP and MEN1 mutations by sequencing.

Results: Two of 21 pituitary adenoma families (9.5%) were found to harbor an AIP deletion. No copy number changes were detected among 67 sporadic pituitary adenoma patients. No MEN1 deletions were found.

Conclusions: The present study shows that large genomic AIP deletions account for a subset of PAP. Therefore, in suspected PAP cases undergoing counseling and AIP genetic testing, multiplex ligation-dependent probe amplification could be considered if direct sequencing does not identify a mutation.

	Introduction

Top Abstract Introduction Subjects and Methods Results and Discussion References

 
Pituitary adenomas account for approximately 15% of all intracranial tumors (1). The majority of pituitary adenomas arise sporadically, although a small subset occurs as a component of familial cancer syndromes, such as multiple endocrine neoplasia type 1 (MEN1) and Carney complex (2, 3). A novel pituitary adenoma susceptibility gene, AIP (11q13) (aryl hydrocarbon receptor interacting protein), has been recently identified. Germline mutations in AIP cause a low-penetrance pituitary adenoma predisposition (PAP) (4), with particularly high relative risk of somatotropinomas. Since AIP identification, novel AIP mutations have been reported in different populations, both in sporadic and familial settings (4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14). Typically, PAP patients have a young age at disease onset, without a strong family history of pituitary adenomas. Occurrence of truncating germline mutations, loss of the normal allele in tumors, and functional evidence suggest that AIP acts as a tumor suppressor gene (4, 6, 11).

Germline mutation analysis of AIP is a powerful tool for presymptomatic recognition of PAP. However, the conventional DNA test for AIP mutations, in which exons and their flanking sequences are amplified and sequenced, is expected to miss some mutation types such as large deletions.

A number of single-exon and partial/whole-gene deletions detected in several tumor suppressor genes have been reported to cause hereditary tumor susceptibility. These include genes underlying, for example, colorectal cancer (MLH1 and MSH2) (15, 16), breast and ovarian cancer (BRCA1 and BRCA2) (17), and MEN1 (MEN1) (18). The development of the multiplex ligation-dependent probe amplification (MLPA) technique has emerged as a significant methodological advance for identification of these large genomic rearrangements (19).

Previously, MLPA with custom-made probes was applied for the study of somatic changes in pituitary tumors (10). Yet, studies searching for germline copy number changes in AIP have not been reported to our knowledge. Here, by using MLPA, we addressed the question as to whether and to what extent copy number changes account for pituitary adenoma cases in patients who have previously tested negative by sequencing for other types of intragenic AIP mutations.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results and Discussion References

 
Subjects

The probands from 23 families with pituitary adenomas from the United Kingdom (n = 8), Italy (n = 7), Finland (n = 5), Germany (n = 1), Turkey (n = 1), and United States (n = 1) were included in the study. Eleven families were heterogeneous (different types of adenomas), and 12 were homogeneous (same type of adenoma), including seven with acromegaly/gigantism, four with nonfunctioning adenomas, and one with prolactinomas (Table 1). In addition, 39 sporadic Finnish GH-secreting adenoma cases aged 40 yr or less at diagnosis and 35 sporadic Italian pediatric pituitary adenoma patients were analyzed. The selection criterion for young age of onset aimed at enriching for possible PAP cases. All patients had previously tested negative for germline AIP and MEN1 mutations by conventional sequencing (6, 14) (unpublished data). Genomic DNA samples from seven healthy, anonymous blood donors were used as negative controls for the MLPA experiments. Ninety-six healthy, unrelated Caucasians (74 United Kingdom, 18 German, and four Centre D’Étude du Polymorphisme Humain individuals) were used as controls for the mutation validation experiments. The study was approved by the appropriate ethics review committees, and proper informed consent was obtained from all subjects.

Gene dosage analysis was carried out using the SALSA MLPA kit P244 designed to detect deletions or amplifications in AIP and MEN1 genes (MRC-Holland, Amsterdam, The Netherlands). The assay was carried out according to manufacturer’s instructions, and the PCR products were run on an ABI3730 DNA sequencer (Applied Biosystems, Foster City, CA). Initially, electropherograms were visualized with the Gene-Marker software version 1.4 (Softgenetics LLC, State College, PA). Data were exported as an Excel-compatible format using Peak Scanner software version 1.0 (Applied Biosystems). Final gene dosage analysis was performed according to manufacturer’s instructions with Coffalyser version 6.0 (MRC-Holland). Probes with a dosage quotient less than 0.65–0.7 (for deletions) or higher than 1.3–1.35 (for amplifications) were examined for consistency by repeated testing. Negative controls (no-DNA controls) were included throughout the MLPA experiments.

PCR/long-range PCR (LR-PCR) and direct sequencing

Deletions detected by MLPA were confirmed by LR-PCR from peripheral blood-extracted DNA or lymphoblastoid cell line-extracted DNA. Fragments were amplified on the genomic DNA level by Phusion DNA Polymerase (Finnzymes, Espoo, Finland) or on cDNA level by AmpliTaq Gold (Applied Biosystems). Primer sequences are available as supplemental material (published as supplemental data on The Endocrine Society’s Journals Online web site at http://jcem.endojournals.org), whereas PCR protocols and conditions are available on request. PCR products corresponding to aberrant alleles were extracted either from 1% low-melt agarose gel (Bio-Rad Laboratories, Hercules, CA) or 1% SeaKem LE Agarose gel (Lonza, Rockland, ME), using QIAquick Gel Extraction Kit (QIAGEN GmbH, Germany) and sequenced using the BigDye 3.1 Termination chemistry on an ABI3730 DNA sequencer (Applied Biosystems). Sequencing primers used for determining deletion breakpoints are provided as supplemental material.

In silico search for Alu repeats

The whole genomic region of AIP and 2 kb upstream of the 5' untranslated region (UTR) (NCBI36:11:67,005,097:67,015,750 and Ensembl release 48, December 2007) was scanned for Alu repeats using the GEMS Launcher–ModelInspector software (release 5.4.3, May 2007) (Genomatix Software GmbH, Munich, Germany) and the Repeat Masker program (http://www.repeatmasker.org/cgi-bin/WEBRepeatMasker, version 3.1.9). Sequence identities of Alu repeats were evaluated by NCBI BLAST 2 Sequences (BLASTN, version 2.2.17, August 2007).

	Results and Discussion

Top Abstract Introduction Subjects and Methods Results and Discussion References

 
Large genomic deletions have been reported in endocrine-related cancer susceptibility genes, such as MEN1 (18) and PRKAR1A (20); however, this issue has remained unresolved for AIP. Twenty-three familial cases, previously tested negative for germline AIP and MEN1 mutations by conventional sequencing (Table 1), were included in this study; 21 of 23 (91%) were successfully analyzed. Two of 21 families (9.5%) were found to harbor one distinct deletion each (Table 1).

A heterozygous AIP exon 2 deletion (Ex2del) was found in the index case of a British family and subsequently in his affected brother (Table 1 and Fig. 1A). The proband had been diagnosed at the age of 18 yr with a nonfunctioning pituitary adenoma (NFPA), and two years later his younger brother was diagnosed at 18 yr with a GH-secreting adenoma. The brothers’ youngest sister, who is currently 16 yr old, remains unaffected. Interestingly, the siblings’ mother had had a spinal ependymoma diagnosed at the age of 41 yr and leading to death four years later. A maternal second cousin has been also diagnosed with an NFPA, but no detailed clinical or genetic data are available. No tumor samples were available for further study. Detailed clinical, biochemical, or genetic analyses have not been performed in the pedigree yet. So far, only few non-GH-secreting adenoma cases have been reported to carry germline AIP mutations (5, 6, 12). This family adds further support to the notion that AIP mutations can underlie pituitary adenomas other than GH-, prolactin (PRL)-, or mixed GH/PRL-secreting lesions.

View larger version (62K): [in this window] [in a new window]   FIG. 1. A, MLPA ratio chart from the proband with the AIP Ex2del. Reduced signal intensity corresponds to a heterozygous deletion of exon 2. B, MLPA ratio chart from the proband with the AIP Ex1_2del. Reduced signal intensity corresponds to a heterozygous deletion of exons 1 and 2. C, Schematic representation of the 5' genomic AIP sequence, indicating Alu repeats (solid black arrows) flanking AIP exons 1, 2, and 3; the deleted fragments of 1562 and 5818 bp are also indicated. D, Sequence electropherogram of AIP Ex2del on genomic DNA level. E, AIP Ex2del on cDNA level. F, Sequence electropherogram of AIP Ex1_2del on genomic DNA level. Arrows in D–F indicate the deletion breakpoints. chr11, Chromosome 11.

The second AIP deletion was detected in the proband of a previously reported German family with two acromegaly patients (4, 22). The proband has been tumor free since 1998 and with no medication and normal serum IGF-I and GH levels since 2004. According to MLPA findings, this heterozygous deletion encompasses exons 1 and 2, including the 5'-UTR (Ex1_2del). Independent MLPA experiments confirmed the presence of the deletion also in her affected son (Fig. 1B). In 2001, and after two pituitary surgeries, her son continued showing signs of acromegaly and had elevated serum IGF-I, GH, and PRL values; he underwent a third surgery, therapy with Sandostatin long-acting release 20 mg, and radiotherapy since 2007. However, no tumor samples are available for further studies.

We hypothesized that this deletion might also occur due to Alu-mediated recombination between the Alu repeats upstream of the 5'-UTR and the repeats downstream of exon 2, in IVS2 (Fig. 1C). LR-PCR on genomic DNA level revealed an aberrant band in both patients, which was not detected among 22 healthy Caucasian controls. From agarose gel analysis, it seemed that a fragment of about 6 kb is deleted; indeed, sequencing of the aberrant allele revealed a deletion of 5818 bp, encompassing 1104 bp upstream of the 5'-UTR and 578 bp of IVS2 (Fig. 1, C and E). The deletion breakpoints did not occur within Alu repeats, but in close proximity, suggesting their involvement. Deletion of the 5' end of the gene, encompassing exons 1 and 2, is predicted to be functionally equivalent to a whole gene deletion, because the translation initiation codon and most likely part of the promoter region is lost.

Copy number changes were not detected either among 32 of 39 (82%) successfully analyzed Finnish GH-secreting adenoma cases, or among 35 Italian pediatric pituitary adenoma patients. Small, intragenic, germline AIP mutations are, in general, rare in sporadic pituitary adenoma patients (6, 10, 13), and the same seems true for large genomic germline alterations. No MEN1 copy number changes were identified.

Previously, an MLPA assay with custom-made probes had been applied for the study of AIP in 41 pituitary tumor samples (10). The AIP locus was deleted in one GH-secreting adenoma specimen; a nonsense mutation (R22X) was identified in the retained allele in the tumor, and also the germline, of the young acromegaly patient. A second large deletion, encompassing both AIP and MEN1 loci, was detected in a second GH-secreting adenoma sample, but no AIP or MEN1 mutation was found in the retained allele (10).

The functional effects of the known human AIP mutations (summarized by family history and mutation type in supplemental Table 2, published as supplemental data on The Endocrine Society’s Journals Online web site at http://jcem.endojournals.org) have not been thoroughly studied yet. Hence, it is not currently clear whether mutations like Ex1_2del cause a more severe phenotype than intragenic mutations that likely result in transcript degradation escape (such as single exon deletions, like AIP Ex2del). In the future, detailed clinical and biochemical examinations of patients carrying these different types of mutations may help reveal information on disease severity, response to drug therapy, or tumor relapse. On a related aspect, it would be of great interest to compare the disease spectrum and penetrance in families with truncating and nontruncating AIP mutations; clearly, much larger patient series and detailed medical investigations would be needed for this.

Overall, in the present cohort, large genomic AIP deletions accounted for two of 21 families (9.5%) when considering all types of pituitary adenomas. In the present study, the 5818-bp deletion accounted for one of seven families (14%) affected with acromegaly only; the 1562-bp deletion accounted for one of nine heterogeneous families (11%). No MEN1 copy number changes were identified among the analyzed probands, compatible with AIP as the major known GH-secreting adenoma susceptibility gene.

The present study shows that large genomic AIP deletions underlie a subset of PAP. In pituitary adenoma patients undergoing AIP genetic testing, MLPA could be applied if genomic sequencing is negative. It is desirable that the detected mutations are further confirmed on genomic DNA or transcript level. MLPA adds to the molecular tools available for detection of PAP. These tools are a prerequisite for adequate identification of the condition in affected individuals as well as identification of the relatives at increased pituitary adenoma risk.

	Acknowledgments

 
We are indebt to all patients and their parents for participation in the study. We are grateful to Rainer Lehtonen for computational support. Sini Marttinen, Inga-Lill Svedberg, and Mikko Aho are acknowledged for excellent technical assistance. We thank Pekka Ellonen for providing sequencing facilities, service, and advice.

	Footnotes

 
This study was supported by the Academy of Finland (the Center of Excellence in Translational Genome-Scale Biology), the Sigrid Jusélius Foundation, the Cancer Society of Finland, the Association for International Cancer Research (A.K.), the Jalmari and Rauha Ahokas Foundation, the Paulo Foundation, the Ida Montin Foundation, the Maud Kuistila Memorial Foundation, the Alexander S. Onassis Public Benefit Foundation (M.G.), and the Helsinki Biomedical Graduate School (E.H.). The sequence data reported herein have the following GenBank database accession numbers: EU872273 (for AIP Ex2del) and EU872274 (for AIP Ex1_2del).

Disclosure Statement: The authors have nothing to disclose.

First Published Online July 15, 2008

Abbreviations: IVS1, Intronic variable sequence 1; LR-PCR, long-range PCR; MEN1, multiple endocrine neoplasia type 1; MLPA, multiplex ligation-dependent probe amplification; PAP, pituitary adenoma predisposition; PRL, prolactin; NFPA, nonfunctioning pituitary adenoma; UTR, untranslated region.

Received May 9, 2008.

Accepted July 9, 2008.

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This Article Abstract Full Text (PDF) Supplemental Data Submit a related Letter to the Editor 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 Georgitsi, M. Articles by Aaltonen, L. A. Search for Related Content PubMed PubMed Citation Articles by Georgitsi, M. Articles by Aaltonen, L. A. Related Collections Neuroendocrinology and Pituitary Endocrine Oncology