Germline CDKN1B/p27(Kip1) mutation in multiple endocrine neoplasia

Georgitsi, Marianthi, Raitila, Anniina, Karhu, Auli, van der Luijt, Rob B., Aalfs, Cora M., Sane, Timo, Vierimaa, Outi, Makinen, Markus J., Tuppurainen, Karoliina, Paschke, Ralph, Gimm, Oliver, Koch, Christian A., Gundogdu, Sadi, Lucassen, Anneke, Tischkowitz, Marc, Izatt, Louise, Aylwin, Simon, Bano, Gul, Hodgson, Shirley, De Menis, Ernesto, Launonen, Virpi, Vahteristo, Pia and Aaltonen, Lauri A. (2007) Germline CDKN1B/p27(Kip1) mutation in multiple endocrine neoplasia. Journal of Clinical Endocrinology & Metabolism, 92 (8), 3321-3325. (doi:10.1210/jc.2006-2843).

Abstract

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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Contributors

Author: Anneke Lucassen

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