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Germline CDKN1B/p27^Kip1 Mutation in Multiple Endocrine Neoplasia

Department of Medical Genetics (M.G., A.R., A.K., V.L., P.V., L.A.A.), 00014 University of Helsinki, Finland; Department of Medical Genetics (R.B.v.d.L.), University Medical Centre Utrecht, 3508 GA Utrecht, The Netherlands; Department of Clinical Genetics (C.M.A.), Academic Medical Centre, 1105 AZ Amsterdam, The Netherlands; Department of Endocrinology (T.S.), Helsinki University Central Hospital, 00029 Helsinki, Finland; Department of Clinical Genetics (O.V.), Oulu University Hospital, 90029 Oulu, Finland; Department of Pathology (M.J.M., K.T.), University of Oulu, 90014 Oulu, Finland; Medical Department III (R.P.), Leipzig University, 04103 Leipzig, Germany; Department of Surgery (O.G.), Martin Luther University Halle-Wittenberg, 06120 Halle, Germany; Division of Endocrinology (C.A.K.), University of Mississippi Medical Center, Jackson, Mississippi 39216; Division of Endocrinology-Metabolism and Diabetes (S.G.), Cerrahpaa Medical Faculty, University of Istanbul, 34303 Istanbul, Turkey; Wessex Clinical Genetics Service (A.L.), Princess Anne Hospital, SO16 5YA Southampton, United Kingdom; Departments of Human Genetics, Oncology, and Medicine (M.T.), McGill University, Sir Mortimer B. Davis Jewish General Hospital, Montreal, Quebec, Canada H3T 1E2; 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 Department of Internal Medicine (E.D.M.), General Hospital, 31100 Treviso, Italy

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

	Abstract

Top Abstract Introduction Subjects and Methods Results and Discussion References

 
Context: Germline mutations in the MEN1 gene predispose to multiple endocrine neoplasia type 1 (MEN1) syndrome, but in up to 20–25% of clinical MEN1 cases, no MEN1 mutations can be found. Recently, a germline mutation in the CDKN1B gene, encoding p27^Kip1, was reported in one suspected MEN1 family with two acromegalic patients.

Objective: Our objective was to evaluate the role of CDKN1B/p27^Kip1 in human tumor predisposition in patients clinically suspected of MEN1 but testing negative for MEN1 germline mutation as well as in familial and sporadic acromegaly/pituitary adenoma patients.

Design: Genomic DNA was analyzed for germline mutations in the CDKN1B/p27^Kip1 gene by PCR amplification and direct sequencing.

Setting: The study was conducted at nonprofit academic research and medical centers.

Patients: Thirty-six Dutch and one German suspected MEN1 patient, who previously tested negative for germline MEN1 gene mutations, were analyzed. In addition, 19 familial and 50 sporadic acromegaly/pituitary adenoma patients from Europe and the United States were included in the study.

Main Outcome Measures: We analyzed germline CDKN1B/p27^Kip1 mutations in individuals with pituitary adenoma and MEN1-like features.

Results: A heterozygous 19-bp duplication (c.59_77dup19) leading to a truncated protein product was identified in one Dutch patient with suspected MEN1 phenotype, pituitary adenoma, carcinoid tumor, and hyperparathyroidism (one of 36, 2.8%). No mutations were detected in either familial or sporadic acromegaly/pituitary adenoma patients.

Conclusions: Our results support the previous finding that germline CDKN1B/p27^Kip1 mutations predispose to a human MEN1-like condition. However, such mutations appear uncommon in suspected MEN1 cases and rare or nonexistent in familial or sporadic acromegaly/pituitary adenoma patients.

	Introduction

Top Abstract Introduction Subjects and Methods Results and Discussion References

 
MULTIPLE ENDOCRINE NEOPLASIA (MEN) is an autosomal dominant disorder characterized by the occurrence of hyperplasia or tumors in at least two endocrine glands in one individual. MEN syndrome can be further divided into subtypes according to the tumor spectrum. MEN1 patients typically develop multiple parathyroid adenomas, pancreatic islet cell neoplasias, and anterior pituitary adenomas (1). MEN1, a tumor suppressor gene coding for the menin protein, has been identified as the gene predisposing to the disorder (2). MEN2 is caused by germline mutations in the RET oncogene (3). The tumor spectrum in MEN2 consists of medullary thyroid carcinomas, pheochromocytomas, and parathyroid adenoma/hyperplasia (4). A subset of patients with MEN do not harbor mutations in the coding regions of the previously identified genes; for instance, in up to 20–25% of patients fulfilling MEN1 criteria, no MEN1 mutations have been identified (5, 6, 7, 8, 9, 10). Some of these patients may have a yet unidentified mutation in the MEN1 gene or mutations in other predisposition genes.

Recently, Pellegata et al. (11) identified a homozygous germline mutation in Cdkn1b, the gene coding for the cyclin-dependent kinase inhibitor p27, in the rat MENX syndrome. The p27^Kip1 protein regulates the cell cycle progression by binding to and inhibiting cyclin/Cdk complexes. Due to its function in the heart of the cell cycle, p27^Kip1 participates in determining several cell fate decisions, including proliferation, differentiation, and apoptosis. MENX is a recessive MEN-like syndrome that has phenotypic features of both human MEN1 and MEN2. p27^Kip1-knockout rats develop various tumors of the neuroendocrine system, including pheochromocytomas, paragangliomas, thyroid cell neoplasias, and parathyroid and pituitary adenomas. Interestingly, the authors also reported one germline nonsense mutation W76X in the human CDKN1B gene in a suspected MEN1 patient with no mutations in the MEN1 gene (11). The index patient had had a pituitary adenoma at the age of 30 yr and was later diagnosed with acromegaly and primary hyperparathyroidism. The mutation was inherited from her father who had also had acromegaly. The proband’s sister, who was diagnosed with renal angiomyolipoma, a MEN1-associated nonendocrine tumor, also carried the mutation. No loss of the wild-type allele was observed in the angiomyolipoma tissue, and both alleles were expressed at the mRNA level. However, p27^Kip1 staining revealed lack of the protein in the tumor tissue (11). In the cell model, the mutation W76X was shown to prevent the protein from entering the nucleus where it normally binds to cyclin/Cdk complexes and inhibits cell cycle progression. These results suggest that CDKN1B/p27^Kip1 may act as a tumor suppressor gene.

p27^Kip1-deficient rats showed increased body weight compared with p27^Kip1+/+ littermates (11, 12). Also, in mice, targeted disruption of the p27^Kip1 leads to a gene-dose-dependent increase in animal size, the adults being 20–30% larger than their wild-type littermates (13, 14, 15). This increased size that was observed in several tissues is due to increased cell proliferation as opposed to increased cell size. The only tumors that spontaneously developed in p27^Kip1–/– mice were pituitary adenomas in the intermediate lobe of the pituitary gland. In another study, p27^Kip1-deficient mice, expressing the metallothionine promoter-driven human GHRH (MT-hGHRH) transgene, exhibited earlier-onset GHRH-induced somatotroph tumors of increased penetrance. This suggests a protective role of p27^Kip1 against the proliferative and tumorigenic action of excessive GHRH (16). In humans, a phenotype with increased body size (gigantism) and the enlargement of the extremities (acromegaly) are seen in individuals with GH-secreting pituitary tumors. Aryl hydrocarbon receptor interacting protein (AIP), a third gene causing endocrine neoplasia susceptibility by germline mutations, was recently identified to predispose to pituitary adenomas and acromegaly (17, 18). AIP is a low-penetrance tumor susceptibility gene that was found to account for a subset of patients diagnosed at young age.

Because only one human CDKN1B/p27^Kip1 germline mutation was presented in the previous work (11), it was relevant to seek further evidence and to examine the possible contribution of CDKN1B/p27^Kip1 mutations in suspected MEN1 cases and pituitary adenoma susceptibility. We addressed the question by performing a germline CDKN1B/p27^Kip1 mutation analysis in a series of 37 patients clinically suspected for MEN1 who had tested negative for MEN1 mutations as well as in 19 patients with familial and 50 patients with sporadic pituitary adenomas.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results and Discussion References

 
Subjects

Thirty-six Dutch individuals clinically suspected for MEN1 and tested negative for the MEN1 gene had been previously analyzed for AIP mutations (18). The same set of samples was used for the CDKN1B/p27^Kip1 mutation analysis. In addition, one suspected MEN1 patient from Germany, who tested negative for MEN1, was included in the study. Although all these patients had undergone MEN1 mutation analysis in clinical practice because of suspected MEN1, it must be emphasized that in many of the cases, the suspicion appears to have been based on limited evidence, and the phenotypes involved are typically not dramatic (supplemental Table 1, published as supplemental data on The Endocrine Society’s Journals Online web site at http://jcem.endojournals.org).

Altogether, 19 patients with familial acromegaly/pituitary adenoma, but no detectable MEN1 or AIP mutations, were also studied (17) (Georgitsi, M., A. Raitila, A. Karhu, R. B. van der Luijt, O. Vierimaa, R. Paschke, A. Lucassen, L. Izatt, S. Hodgson, E. De Menis, V. Launonen, P. Vahteristo, L. A. Aaltonen, and V. K. Ajith Kumar, unpublished data) (supplemental Table 2, published as supplemental data on The Endocrine Society’s Journals Online web site).

In addition, 50 sporadic Finnish acromegaly patients were analyzed. Thirty-four patients had been selected based on young age at diagnosis (<45 yr), diagnosed at the Department of Endocrinology, Helsinki University Central Hospital, Helsinki, Finland. Sixteen patients had been diagnosed at the Oulu University Hospital, Oulu, Finland (17, 18) (Georgitsi, M., A. Raitila, A. Karhu, O. Vierimaa, M. J. Mäkinen, V. Launonen, P. Vahteristo, and L. A. Aaltonen, unpublished data).

A DNA panel representing 96 Caucasians (Human Random Control DNA Panels, Porton Down, Salisbury, Wiltshire, UK) was used as source for controls. The study was approved by the appropriate ethics review committees. Appropriate informed consent was obtained from all subjects.

Mutation analysis

DNA extracted from peripheral blood and paraffin-embedded tumor tissue was analyzed for CDKN1B/p27^Kip1 mutations by direct sequencing. Primer sequences are presented in supplemental Table 3 (published as supplemental data on The Endocrine Society’s Journals Online web site), and PCR conditions are available upon request. DNA sequencing was performed using the Big Dye 3.1 Termination chemistry on an ABI3730 DNA sequencer (Applied Biosystems, Foster City, CA).

p27^Kip1 immunohistochemistry (IHC)

Four-micrometer-thick sections were cut from the paraffin-embedded tissue specimens and hydrated overnight at 37 C. After deparaffinization, rehydration in graded alcohol series, and rinses with PBS, antigen retrieval was carried through with 0.01 M Tris-EDTA in a microwave oven at 850 W for 2 min and at 150 W for 10 min. Thereafter, sections were allowed to cool for 20 min and rinsed with PBS. Dako EnVision blocking solution (Dako Inc., Copenhagen, Denmark) was used to block endogenous activity. After three rinses in PBS, slides were incubated in primary antibody (p27^Kip1, clone 57; BD Biosciences, San Jose, CA) at a dilution of 1:500 for 30 min at room temperature. Sections were rinsed with PBS three times, and bound antibodies were detected using the EnVision system (Dako). Concentrated 3,3'-diaminobenzidine chromogen was used to observe the localization of immunoreaction. Finally, sections were counterstained with hematoxylin, dehydrated in graded alcohol series, embedded in xylol, and covered.

In silico analysis

The potential effect on splicing of one silent change was predicted in silico by computational methods, using NetGene2 (http://www.cbs.dtu.dk/services/NetGene2), Alternative Splice Site Predictor (http://es.embnet.org/mwang/assp.html), and Splice-Scan (http://bioinformatics.ist.unomaha.edu/achurban/SpliceScan/ScoreDonor.html and http://bioinformatics.ist.unomaha.edu/achurban/SpliceScan/ScoreAcceptor.html) programs.

	Results and Discussion

Top Abstract Introduction Subjects and Methods Results and Discussion References

 
The CDKN1B/p27^Kip1 gene was recently identified as a new susceptibility gene for a MEN1-like condition, in one family segregating endocrine neoplasia (11). Here we report a second patient with a germline CDKN1B/p27^Kip1 mutation. The mutation was identified in one of 36 (2.8%) Dutch patients clinically suspected for MEN1. The mutation is a 19-bp duplication (c.59_77dupAGGCGGAGCACCCCAAGCC) in exon 1, which changes the amino acid sequence after 26 residues and leads to a premature stop codon 69 amino acids earlier than the wild type (Fig. 1, A and B). The mutation was not detected in 96 healthy controls. This female patient has been diagnosed with three lesions compatible with MEN1: small-cell neuroendocrine cervical carcinoma at the age of 45 yr, ACTH-secreting pituitary adenoma (Cushing’s disease) at the age of 46 yr, and hyperparathyroidism at the age of 47 yr. In addition, she was diagnosed with multiple sclerosis at the age of 46 yr. Tumor tissue was available from the neuroendocrine cervical carcinoma. Loss of heterozygosity analysis revealed loss of the wild-type allele in the tumor (Fig. 2A), and also the IHC showed negative p27^Kip1 staining (Fig. 2, B and C). None of the patient’s first-degree family members (parents and four siblings) were affected with MEN1-related lesions. DNA from one unaffected brother was available for mutation analysis, and he was found not to be a mutation carrier.

View larger version (49K): [in this window] [in a new window]   FIG. 1. Germline CDKN1B/p27Kip1 mutation in a suspected MEN1 patient. A, The upper panel shows the wild-type sequence around the c.59_77dup19 mutation (duplicated sequence underlined). In the lower panel, the starting point of the mutation is indicated by an arrow. B, Alignment of the p27Kip1 wild-type and mutant amino acid sequences. The mutation changes the amino acid sequence after 26 residues and leads to a premature termination codon 69 amino acids earlier than the wild type.

View larger version (114K): [in this window] [in a new window]   FIG. 2. Loss of heterozygosity analysis and immunohistochemical staining of the small-cell neuroendocrine cervical carcinoma tissue from the CDKN1B/p27Kip1 c.59_77dup19 mutation-positive individual. A, Complete loss of the wild-type allele (the 19 duplicated base pairs are underlined); B, p27Kip1 expression in normal cervical tissue, used as positive immunoreaction control; C, p27Kip1-deficient cervical carcinoma, bearing the c.59_77dup19 mutation. There is complete loss of p27Kip1 immunoreaction.

No pathogenic mutations were detected in 19 familial or 50 sporadic patients with solitary acromegaly/pituitary adenoma. The only variation was a previously observed silent c.426GA (T142T) change in one young sporadic acromegaly patient (19, 20). The variant is located outside the functional domains, 50 bp upstream of the exon-intron boundary. According to in silico analysis, c.426GA has no effect on splicing. The common polymorphism c.326TG (V109G) in CDKN1B/p27^Kip1 exon 1 was present in both suspected MEN1 and pituitary adenoma cases, with frequencies similar to those previously observed (19) (www.hapmap.org).

Sporadic pituitary tumors have been screened for CDKN1B/p27^Kip1, but no somatic mutations have been detected (21, 22). Furthermore, mRNA expression levels seem to remain unaltered between tumorous and nontumorous pituitaries; however, the p27^Kip1 protein expression level in pituitary adenomas seems to be significantly reduced during progression from normal to neoplastic pituitaries, although the findings are not totally concordant (21, 22, 23, 24). Corticotroph cells represent an exception from this pattern because both normal and tumorous ACTH-producing cells show very low p27^Kip1 expression, which virtually disappears from ACTH-secreting adenomas (23). These results suggest that the contribution of CDKN1B/p27^Kip1 mutations to the development of human sporadic pituitary adenomas is limited and that posttranslational mechanisms are involved in their pathogenesis.

The role of CDKN1B/p27^Kip1 in other tumor types has also been studied, but only few somatic mutations have been identified in hundreds of tumor samples analyzed (21, 25). However, down-regulation of p27^Kip1 expression has been observed in all human malignancies thus far examined, with frequent association with reduced survival (25). Again, the expression seems to be primarily regulated at the posttranscriptional level, affecting mainly the protein translation, stability, or localization.

Our results support the previous observation that germline mutations in the CDKN1B/p27^Kip1 gene can be found in MEN1-like patients. Such mutations seem very rare (19) (this study), but many of our patients had mild phenotypes, and mutations may be more frequent if more dramatic phenotypes were examined. Identification of CDKN1B/p27^Kip1 and AIP as novel endocrine neoplasia susceptibility genes adds to our knowledge of the genesis of these tumors. Increased awareness may facilitate the counseling and clinical management of patients with MEN phenotypes.

	Acknowledgments

 
All patients are greatly acknowledged for their valuable help. S. Marttinen, I.-L. Svedberg, I. Vuoristo, C. Gomez-Sanchez, and A. Parent are gratefully acknowledged for excellent technical assistance, and P. Ellonen for providing sequencing facilities and service.

	Footnotes

 
This study was supported by the Academy of Finland (Grants 213183, 212901, and the Center of Excellence in Translational Genome-Scale Biology), the Sigrid Jusélius Foundation, the Cancer Society of Finland, the Association for International Cancer Research (Grant 05-001 to A.K.), the Jalmari and Rauha Ahokas Foundation (to M.G.), and the Bodossaki Foundation (to M.G.).

The sequence data reported herein has the following GenBank database accession no.: EF474465.

Disclosure Statement: The authors have nothing to disclose.

First Published Online May 22, 2007

¹ M.G. and A.R. contributed equally to this work.

Abbreviations: IHC, Immunohistochemistry; MEN, multiple endocrine neoplasia.

Received December 21, 2006.

Accepted May 10, 2007.

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