title: Germline CDKN1B/p27Kip1 mutation in multiple endocrine neoplasia.
abstract: BACKGROUND
  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.
  
  
  METHODS
  Genomic DNA was analyzed for germline mutations in the CDKN1B/p27(Kip1) gene by PCR amplification and direct sequencing.
  
  
  METHODS
  The study was conducted at nonprofit academic research and medical centers.
  
  
  METHODS
  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.
  
  
  METHODS
  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.
authors.affiliation: Department of Medical Genetics, University of Helsinki, Finland.
authors.forename: Marianthi
authors.initials: M
authors.lastname: Georgitsi
authors.forename: Anniina
authors.initials: A
authors.lastname: Raitila
authors.forename: Auli
authors.initials: A
authors.lastname: Karhu
authors.forename: Rob B
authors.initials: RB
authors.lastname: van der Luijt
authors.forename: Cora M
authors.initials: CM
authors.lastname: Aalfs
authors.forename: Timo
authors.initials: T
authors.lastname: Sane
authors.forename: Outi
authors.initials: O
authors.lastname: Vierimaa
authors.forename: Markus J
authors.initials: MJ
authors.lastname: Mäkinen
authors.forename: Karoliina
authors.initials: K
authors.lastname: Tuppurainen
authors.forename: Ralph
authors.initials: R
authors.lastname: Paschke
authors.forename: Oliver
authors.initials: O
authors.lastname: Gimm
authors.forename: Christian A
authors.initials: CA
authors.lastname: Koch
authors.forename: Sadi
authors.initials: S
authors.lastname: Gündogdu
authors.forename: Anneke
authors.initials: A
authors.lastname: Lucassen
authors.forename: Marc
authors.initials: M
authors.lastname: Tischkowitz
authors.forename: Louise
authors.initials: L
authors.lastname: Izatt
authors.forename: Simon
authors.initials: S
authors.lastname: Aylwin
authors.forename: Gul
authors.initials: G
authors.lastname: Bano
authors.forename: Shirley
authors.initials: S
authors.lastname: Hodgson
authors.forename: Ernesto
authors.initials: E
authors.lastname: De Menis
authors.forename: Virpi
authors.initials: V
authors.lastname: Launonen
authors.forename: Pia
authors.initials: P
authors.lastname: Vahteristo
authors.forename: Lauri A
authors.initials: LA
authors.lastname: Aaltonen
mesh_terms: D000595:Amino Acid Sequence; D003198:Computer Simulation; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004247:DNA / Q000235:genetics*; D004252:DNA Mutational Analysis; D018095:Germ-Line Mutation; D006801:Humans; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008969:Molecular Sequence Data; D018761:Multiple Endocrine Neoplasia Type 1 / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C436291:CDKN1B protein, human; D047908:Intracellular Signaling Peptides and Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004247:DNA