title: A novel deletion of the MEN1 gene in a large family of multiple endocrine neoplasia type 1 (MEN1) with aggressive phenotype.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: Department of Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
authors.forename: Hussein
authors.initials: H
authors.lastname: Raef
authors.forename: Minjing
authors.initials: M
authors.lastname: Zou
authors.forename: Essa Y
authors.initials: EY
authors.lastname: Baitei
authors.forename: Roua A
authors.initials: RA
authors.lastname: Al-Rijjal
authors.forename: Namik
authors.initials: N
authors.lastname: Kaya
authors.forename: Mohamed
authors.initials: M
authors.lastname: Al-Hamed
authors.forename: Dorota
authors.initials: D
authors.lastname: Monies
authors.forename: Nada N
authors.initials: NN
authors.lastname: Abu-Dheim
authors.forename: Hindi
authors.initials: H
authors.lastname: Al-Hindi
authors.forename: Mohammed H
authors.initials: MH
authors.lastname: Al-Ghamdi
authors.forename: Brian F
authors.initials: BF
authors.lastname: Meyer
authors.forename: Yufei
authors.initials: Y
authors.lastname: Shi
mesh_terms: D007516:Adenoma, Islet Cell / Q000235:genetics; D000293:Adolescent; D000328:Adult; D002648:Child; D005190:Family; D005260:Female; D017353:Gene Deletion; D056726:Genetic Association Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D018761:Multiple Endocrine Neoplasia Type 1 / Q000235:genetics*; D010190:Pancreatic Neoplasms / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D017422:Sequence Analysis, DNA; D055815:Young Adult
chemical_list: C105373:MEN1 protein, human; D011518:Proto-Oncogene Proteins