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This version published online on May 22, 2007
Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2006-2843
A more recent version of this article appeared on August 1, 2007
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Submitted on December 21, 2006
Accepted on May 10, 2007

Germline CDKN1B/p27Kip1 mutation in multiple endocrine neoplasia

Marianthi Georgitsi, Anniina Raitila, Auli Karhu, Rob B. van der Luijt, Cora M. Aalfs, Timo Sane, Outi Vierimaa, Markus J. Mäkinen, Karoliina Tuppurainen, Ralph Paschke, Oliver Gimm, Christian A. Koch, Sadi Gündogdu, Anneke Lucassen, Marc Tischkowitz, Louise Izatt, Simon Aylwin, Gul Bano, Shirley Hodgson, Ernesto De Menis, Virpi Launonen, Pia Vahteristo, and Lauri A. Aaltonen*

Department of Medical Genetics, University of Helsinki, 00014 University of Helsinki, Finland; Department of Medical Genetics, University Medical Centre Utrecht, 3508 GA Utrecht, The Netherlands; Department of Clinical Genetics, Academic Medical Centre, 1105 AZ Amsterdam, The Netherlands; Department of Endocrinology, Helsinki University Central Hospital, 00029 Helsinki, Finland; Department of Clinical Genetics, Oulu University Hospital, 90029 Oulu, Finland; Department of Pathology, University of Oulu, 90014 Oulu, Finland; Medical Department III, Leipzig University, 04103 Leipzig, Germany; Department of Surgery, Martin-Luther-University Halle-Wittenberg, 06120 Halle, Germany; Division of Endocrinology, University of Mississippi Medical Center, 2500 N State Street, 39 216 Jackson, MS, USA; Division of Endocrinology-Metabolism and Diabetes, Cerrahpa|fcsa Medical Faculty, University of Istanbul, 34303 Istanbul, Turkey; Wessex Clinical Genetics Service, Princess Anne Hospital, SO16 5YA Southampton, United Kingdom; Departments of Human Genetics, Oncology and Medicine, McGill University, Sir Mortimer B. Davis Jewish General Hospital, 3755 Côte Ste Catherine Road, H3T 1E2 Montreal QC, Canada; Department of Clinical Genetics, New Guy's House, Guy's Hospital, London SE1 9RT, United Kingdom; Department of Medicine, King's College Hospital, Denmark Hill, London SE5 9RS, United Kingdom; Department of Endocrinology and Diabetes, Thomas Addison unit, Blackshaw Road, London SW17 0QT, United Kingdom; Department of Clinical Genetics, St. Georges, University of London, Cranmer Terrace, London SW17 ORE, United Kingdom; Department of Internal Medicine, General Hospital, 31100 Treviso, Italy

* To whom correspondence should be addressed. E-mail: lauri.aaltonen{at}helsinki.fi.

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 Cyclin-dependent kinase inhibitor 1B (CDKN1B), encoding p27Kip1, was reported in one suspected MEN1 family with two acromegalic patients.

Objective: To evaluate the role of CDKN1B/p27Kip1 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/p27Kip1 gene by PCR amplification and direct sequencing.

Setting: Non-profit academic research and medical centers.

Patients: Thirty-six Dutch and one German suspected MEN1 patients, 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 USA were included in the study.

Main Outcome Measures: Analysis of germline CDKN1B/p27Kip1 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 (1/36, 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/p27Kip1 mutations predispose to a human MEN1-like condition. However, such mutations appear uncommon in suspected MEN1 cases and rare or non-existent in familial or sporadic acromegaly/pituitary adenoma patients.
Key words: Pituitary adenomas • Multiple Endocrine Neoplasia Type 1 (MEN1) • MEN1 • CDKN1B • p27Kip1




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