Germline CDKN1B/p27Kip1 mutation in multiple endocrine neoplasia.
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.
Georgitsi
Marianthi
M
Department of Medical Genetics, University of Helsinki, Finland.
Raitila
Anniina
A
Karhu
Auli
A
van der Luijt
Rob B
RB
Aalfs
Cora M
CM
Sane
Timo
T
Vierimaa
Outi
O
Mäkinen
Markus J
MJ
Tuppurainen
Karoliina
K
Paschke
Ralph
R
Gimm
Oliver
O
Koch
Christian A
CA
Gündogdu
Sadi
S
Lucassen
Anneke
A
Tischkowitz
Marc
M
Izatt
Louise
L
Aylwin
Simon
S
Bano
Gul
G
Hodgson
Shirley
S
De Menis
Ernesto
E
Launonen
Virpi
V
Vahteristo
Pia
P
Aaltonen
Lauri A
LA
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
C436291:CDKN1B protein, human; D047908:Intracellular Signaling Peptides and Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004247:DNA