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A novel deletion of the MEN1 gene in a large family of multiple endocrine neoplasia type 1 (MEN1) with aggressive phenotype
Author(s) -
Raef Hussein,
Zou Minjing,
Baitei Essa Y.,
AlRijjal Roua A.,
Kaya Namik,
AlHamed Mohamed,
Monies Dorota,
AbuDheim Nada N.,
AlHindi Hindi,
AlGhamdi Mohammed H.,
Meyer Brian F.,
Shi Yufei
Publication year - 2011
Publication title -
clinical endocrinology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.055
H-Index - 147
eISSN - 1365-2265
pISSN - 0300-0664
DOI - 10.1111/j.1365-2265.2011.04134.x
Subject(s) - men1 , biology , multiple endocrine neoplasia , multiplex ligation dependent probe amplification , loss of heterozygosity , genomic imprinting , dna methylation , genetics , locus (genetics) , exon , comparative genomic hybridization , microbiology and biotechnology , cancer research , gene , chromosome , gene expression , allele
Summary 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.