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Mutational analyses of WNT7A and HDAC11 as candidate tumour suppressor genes in sporadic malignant pancreatic endocrine tumours
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences. (Endokrinkirurgi)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences. (Endokrinkirurgi)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
2007 (English)In: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 66, no 1, 110-114 p.Article in journal (Refereed) Published
Abstract [en]

Objective We and others have reported loss of heterozygosity (LOH) on chromosome 3p25 in sporadic malignant pancreatic endocrine tumours (PETs). A common region of deletion on chromosome 3p25 contains numerous genes, including VHL and PPARγ, that have been excluded previously as candidate tumour suppressor genes by DNA sequencing analysis. We have analysed whether WNT7A or HDAC11 was biallelically inactivated in a group of well-characterized PETs.

Patients and design Ten PETs from eight patients were selected from a previous study, where LOH on chromosome 3p25 was found in 11 out of 22 sporadic PETs. These tumours were examined for inactivating mutations of WNT7A and HDAC11 by direct sequencing of all exons and intron–exon boundaries. Inactivation of WNT7A expression by aberrant CpG island methylation and WNT7A protein expression were evaluated by methylation-specific polymerase chain reaction (PCR) and immunohistochemistry, respectively. HDAC11 protein expression was also examined.

Results No point mutations, deletion or insertions were detected in either WNT7A or HDAC11 in any of the PETs. Two polymorphisms were identified in the third exon of the WNT7A gene. CpG methylation of the WNT7A gene was not detected and the WNT7A and HDAC11 proteins were normally expressed.

Conclusion The absence of tumour-specific somatic events in WNT7A and HDAC11 suggests that these genes are unlikely to have a classical tumour suppressor gene role in sporadic malignant PETs. The putative 3p25 tumour suppressor remains to be identified.

Place, publisher, year, edition, pages
2007. Vol. 66, no 1, 110-114 p.
Keyword [en]
pancreatic endocrine tumors
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-95506DOI: 10.1111/j.1365-2265.2006.02694.xISI: 000242780500016PubMedID: 17201809OAI: oai:DiVA.org:uu-95506DiVA: diva2:169748
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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