PMID- 21627674
OWN - NLM
STAT- MEDLINE
DCOM- 20120305
LR  - 20111109
IS  - 1365-2265 (Electronic)
IS  - 0300-0664 (Linking)
VI  - 75
IP  - 6
DP  - 2011 Dec
TI  - A novel deletion of the MEN1 gene in a large family of multiple endocrine 
      neoplasia type 1 (MEN1) with aggressive phenotype.
PG  - 791-800
LID - 10.1111/j.1365-2265.2011.04134.x [doi]
AB  - CONTEXT: The MEN1 syndrome is associated with parathyroid, pancreatic and 
      pituitary tumours and is caused by mutations in the MEN1 gene. In general, there 
      is no genotype-phenotype correlation. OBJECTIVES: To characterize a large family 
      with MEN1 with aggressive tumour behaviour: malignant pancreatic endocrine 
      tumours were present in five affected subjects and were the presenting features 
      in three subjects. DESIGN: The coding region of MEN1 was sequenced. Gene copy 
      number analysis was performed by multiplex ligation-dependent probe amplification 
      (MLPA) and array comparative genomic hybridization (aCGH). Loss of heterozygosity 
      (LOH) in tumour tissue was studied by microsatellite analysis. Insulin-like 
      growth factor II (IGF-II) and CDKN1C/p57KIP2 expression were investigated by 
      immunohistochemistry. RESULTS: Mutation screening by conventional PCR sequence 
      analysis of patients' peripheral blood DNA did not reveal any mutation in the 
      MEN1 or CDKN1B gene. Gene copy number analysis by MLPA and aCGH demonstrated a 
      novel monoallelic deletion of 5 kb genomic DNA involving the MEN1 promoter and 
      exons 1 and 2. LOH analysis indicated somatic deletion of maternal chromosome 11, 
      including MEN1 locus (11q13) and 11p15 imprinting control regions (ICR). 
      Methylation analysis of ICR demonstrated ICR1 hypermethylation and ICR2 
      hypomethylation in the tumour specimens. ICR1 and ICR2 control the expression of 
      IGF-2 and CDKN1C/p57KIP2, respectively. Immunohistochemistry showed that 
      expression of paternally expressed IGF-2 was up-regulated and the maternally 
      expressed CDKN1C/p57KIP2 was lost in the pancreatic endocrine tumours. 
      CONCLUSIONS: Gene copy number analysis by MLPA should be considered in patients 
      with negative conventional mutation screening. Although large MEN1 deletion 
      causes MEN1, disruption of imprinted CDKN1C/p57KIP2 and IGF-2 gene expression may 
      contribute to tumour progression and aggressive phenotype.
CI  - (c) 2011 Blackwell Publishing Ltd.
FAU - Raef, Hussein
AU  - Raef H
AD  - Department of Medicine, King Faisal Specialist Hospital and Research Centre, 
      Riyadh, Saudi Arabia.
FAU - Zou, Minjing
AU  - Zou M
FAU - Baitei, Essa Y
AU  - Baitei EY
FAU - Al-Rijjal, Roua A
AU  - Al-Rijjal RA
FAU - Kaya, Namik
AU  - Kaya N
FAU - Al-Hamed, Mohamed
AU  - Al-Hamed M
FAU - Monies, Dorota
AU  - Monies D
FAU - Abu-Dheim, Nada N
AU  - Abu-Dheim NN
FAU - Al-Hindi, Hindi
AU  - Al-Hindi H
FAU - Al-Ghamdi, Mohammed H
AU  - Al-Ghamdi MH
FAU - Meyer, Brian F
AU  - Meyer BF
FAU - Shi, Yufei
AU  - Shi Y
LA  - eng
PT  - Case Reports
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Clin Endocrinol (Oxf)
JT  - Clinical endocrinology
JID - 0346653
RN  - 0 (MEN1 protein, human)
RN  - 0 (Proto-Oncogene Proteins)
SB  - IM
MH  - Adenoma, Islet Cell/genetics
MH  - Adolescent
MH  - Adult
MH  - Child
MH  - Family
MH  - Female
MH  - Gene Deletion
MH  - Genetic Association Studies
MH  - Humans
MH  - Male
MH  - Middle Aged
MH  - Multiple Endocrine Neoplasia Type 1/*genetics
MH  - Pancreatic Neoplasms/*genetics
MH  - Pedigree
MH  - Phenotype
MH  - Proto-Oncogene Proteins/*genetics
MH  - Sequence Analysis, DNA
MH  - Young Adult
EDAT- 2011/06/02 06:00
MHDA- 2012/03/06 06:00
CRDT- 2011/06/02 06:00
PHST- 2011/06/02 06:00 [entrez]
PHST- 2011/06/02 06:00 [pubmed]
PHST- 2012/03/06 06:00 [medline]
AID - 10.1111/j.1365-2265.2011.04134.x [doi]
PST - ppublish
SO  - Clin Endocrinol (Oxf). 2011 Dec;75(6):791-800. doi: 
      10.1111/j.1365-2265.2011.04134.x.