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Evaluation of CDKN2C/p18, CDKN1B/p27, and CDKN2B/p15 mRNA expression and CpG methylation status in sporadic and MEN1-associated pancreatic endocrine tumors
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences. (Endocrine Surgery)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences. (Endocrine Surgery)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences. (Endocrine Surgery)
2008 (English)In: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 68, no 2, 271-278 p.Article in journal (Refereed) Published
Abstract [en]

Objective Menin, encoded by the multiple endocrine neoplasia type 1 (MEN1) gene at 11q13, enhances transcription of the cyclin-dependent kinase inhibitors (CDIs), CDKN2C (p18) and CDKN1B (p27) in mouse pancreatic islets, and inactivation of menin reduced CDKN2B (p15) expression in this mouse model. Here, we have compared the relative mRNA expression level and CpG methylation status of p18, p27 and p15 in 18 pancreatic endocrine tumours (PETs) with or without MEN1 gene mutations. Design Real-time quantitative PCR, DNA sequencing and pyro-sequencing methylation analysis were employed. Results The p18 gene was expressed in 15 out of the 18 analysed PETs. The expression level was within the range of the normal pancreatic tissues or higher. Of the three remaining tumours with no expression, two displayed loss of heterozygocity (LOH) at 11q13, one derived from a MEN1 patient. The p27 gene was expressed in all PETs at a level higher than the normal pancreatic tissues, except for one tumour. Promoter methylation was not detected for p18 and p27. p15 expression was undetectable in 8/18 (44%) of the PETs, and no general relations to tumour syndrome, malignancy or MEN1 gene mutations were evident. This was not due to homozygous gene deletions, but the p15 promoter was hypermethylated in two insulinomas. No mutations were found in the pl5 gene. Conclusions Expression of p15, p18 and p27 was not generally related to the MEN1 gene mutational status of the investigated 18 PETs. The p15 gene was silenced by promoter hypermethylation in two tumours. Dysregulation of menin and the CDIs are important in PET tumorigenesis, and their interrelations remain to be elucidated.

Place, publisher, year, edition, pages
2008. Vol. 68, no 2, 271-278 p.
Keyword [en]
Digestive diseases, Benign neoplasm, Genetic disease, Endocrinopathy, Endocrine tumor, Pancreatic tumor, Endocrinology, Pancreatic disease, Multiple endocrine neoplasia type I, Sporadic, Methylation, Nucleotide sequence, GC rich sequence, Gene expression, Messenger RNA, Tumor suppressor gene, KIP1 Gene, Evaluation
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-95507DOI: 10.1111/j.1365-2265.2007.03034.xISI: 000252319800017PubMedID: 17803708OAI: oai:DiVA.org:uu-95507DiVA: diva2:169749
Available from: 2007-03-01 Created: 2007-03-01 Last updated: 2017-12-14Bibliographically approved
In thesis
1. Molecular Genetic Studies of Sporadic and MEN1-Associated Endocrine Pancreatic Tumors
Open this publication in new window or tab >>Molecular Genetic Studies of Sporadic and MEN1-Associated Endocrine Pancreatic Tumors
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Pancreatic endocrine tumors (PETs) may cause typical syndromes of hormone excess, or appear clinically non-functioning without hormonal symptoms. PETs occur sporadically, in association with the multiple endocrine neoplasia type 1 (MEN1) syndrome, or rarely the von Hippel-Lindau syndrome. Molecular genetic investigations may reveal pathways important for tumor development, and be of clinical use.

The aim of this thesis was to investigate regulation of different genes involved in cell proliferation, and relate findings to signs of malignancy in PETs.

The MEN1 gene on chromosome 11q13 was mutated in three out of eleven sporadic malignant PETs. Two nonsense mutations, causing truncation of the protein, and one missense mutation were found.

Relation of allelic loss at 11q13 and 3p25 to malignant behavior was observed in sporadic PETs. Allelic loss at 18q21 was found in a subset of sporadic and MEN1-associated PETs, and mutation analysis of Smad4 excluded a tumor suppressor gene function.

In PETs with allelic loss on chromosome 3p25, mutation analysis of WNT7A and HDAC11 excluded function as tumor suppressor genes.

Menin, encoded by the MEN1 gene, was reported to regulate expression of the cyclin-dependent kinase inhibitors CDKN2C/p18, CDKN1B/p27, and CDKN2B/p15 in mouse pancreatic islet tumor models. Here, the mRNA expression of these genes was not related to MEN1 gene mutations in human PETs.

Cyclin-dependent kinase 4 (CDK4) and the protooncogene c-Myc were found to be overexpressed regardless of MEN1 gene mutational status of the PETs. The CDK4 gene was neither amplified nor mutated. Targeting of CDK4 may present an alternative to traditional chemotherapy of PETs in the future.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2007. 65 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 231
Keyword
Surgery, pancreatic endocrine tumor, MEN1, LOH, WNT7A, HDAC11, CDK4, CDKN2B/p15, CDKN1B/p27, CDKN2C/p18, c-Myc, Smad4, pyrosequencing, epigenetic, methylation, tumor suppressor, Kirurgi
Identifiers
urn:nbn:se:uu:diva-7595 (URN)978-91-554-6810-1 (ISBN)
Public defence
2007-03-23, Rosénsalen, Kvinnokliniken, Akademiska sjukhuset ing 95, Uppsala, 13:00
Opponent
Supervisors
Available from: 2007-03-01 Created: 2007-03-01Bibliographically approved

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Lindberg, DanielÅkerström, GöranWestin, Gunnar

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