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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.

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.

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