Germline CDKN1B/p27Kip1 Mutation in Multiple Endocrine Neoplasia

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 p27Kip1, was reported in one suspected MEN1 family with two acromegalic patients. Objective: Our objective was 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: 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/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 (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/p27Kip1 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.