uu.seUppsala University Publications
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Evidence of a stabilizing mutation of beta-catenin encoded by CTNNB1 exon 3 in a large series of sporadic parathyroid adenomas
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Experimental Surgery.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences. (Endokrinkirurgi, Endocrine Surgery)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Experimental Surgery.
Show others and affiliations
2012 (English)In: Endocrine (Basingstoke), ISSN 1355-008X, E-ISSN 1559-0100, Vol. 42, no 3, 612-615 p.Article in journal (Refereed) Published
Abstract [en]

Aberrant accumulation of beta-catenin plays an important role in a variety of human neoplasms. This can be caused by stabilizing mutation of beta-catenin (CTNNB1, exon 3) or by mutation or deregulated expression of other components of the WNT/beta-catenin signaling pathway. Accumulation of non-phosphorylated active beta-catenin has been reported to commonly occur in parathyroid adenomas from patients with primary hyperparathyroidism (pHPT), either due to the aberrantly spliced internally truncated WNT receptor LRP5 (LRP5 Delta) or to a stabilizing mutation of beta-catenin. The S37A mutation was reported to occur in 7.3 % in a single study of parathyroid adenomas, while in other studies no stabilizing mutations of beta-catenin exon 3 were identified. The aim of this study was to determine the mutational frequency of the CTNNB1 gene, specifically exon 3 in a large series of parathyroid adenomas. One hundred and eighty sporadic parathyroid adenomas were examined for mutations in exon 3 of CTNNB1 by direct DNA sequencing, utilizing previously published primer sequences. The mutation S33C (TCT > TGT) was detected by direct-DNA sequencing of PCR fragments in 1 out of 180 sporadic parathyroid adenomas (0.68 %). Like serine 37, mutations of serine 33 have been reported in many neoplasms with resulting beta-catenin stabilization, enhanced transcription, and oncogenic activities. Immunohistochemical analysis revealed an overexpression of the beta-catenin protein in the lone mutant tumor. Taking also previous studies into account we conclude that activating mutations of the regulatory GSK-3 beta phosphorylation sites serine 33 and 37, encoded by CTNNB1 exon 3, rarely occur in parathyroid adenomas from patients with pHPT.

Place, publisher, year, edition, pages
2012. Vol. 42, no 3, 612-615 p.
Keyword [en]
Parathyroid, Primary hyperparathyroidism, Beta-catenin
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-191036DOI: 10.1007/s12020-012-9690-3ISI: 000312073500023OAI: oai:DiVA.org:uu-191036DiVA: diva2:585265
Note

Correction in: Endocrine, vol. 42, issue 3, pg 769

DOI: 10.1007/s12020-012-9763-3

Available from: 2013-01-09 Created: 2013-01-09 Last updated: 2017-12-06
In thesis
1. New Insights in Genetic and Epigenetic Mechanisms Involved in Parathyroid Tumorigenesis
Open this publication in new window or tab >>New Insights in Genetic and Epigenetic Mechanisms Involved in Parathyroid Tumorigenesis
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Primary hyperparathyroidism (pHPT) is a pathology associated with one or multiple hyperfunctioning parathyroid glands.  The disease prevalence occurs in roughly 1-2% of the population primarily post-menopausal women.  The molecular pathology of the disease is poorly understood.  Elevated serum calcium levels in the setting of an inappropriately elevated parathyroid hormone level are indicative of the disease process.  The ultimate treatment of the disease is to remove the hyperfunctioning gland.

The aim of this thesis was to examine potential genetic and epigenetic aberrations that are potentially disease causing.

The methylation signature of normal and pathological parathyroid tissue has yet to be investigated.  DNA was bisulphite modified and analyzed using the Infinium HumanMethylation27 BeadChip. Distinct hierarchical clustering of genes with altered DNA methylation profiles in normal and pathologic parathyroid tissue was evident.  DNA hypermethylation of CDKN2B, CDKN2A, WT1, SFRP1, SFRP2, and SFRP4 known to be important in the development of parathyroid tumors were associated with reduced gene expression in both benign and malignant parathyroid tumors.

Familial primary hyperparathyroidism (FPHPT) may occur due to an underlying germ-line mutation in the MEN1, CASR, or HRPT2/CDC73 genes.  Eighty-six young (45 years of age) patients with clinically non-syndromic PHPT underwent genetic analysis.  Eight of 86 (9.3%) young patients with clinically non-familial PHPT displayed deleterious germ-line mutations in the susceptibility genes (4 MEN1, 3 CASR, and 1 HRPT2/ CDC73).

Accumulation of non-phosphorylated active β -catenin has been reported to commonly occur in parathyroid adenomas from patients with primary hyperparathyroidism (pHPT).  We assessed possible β-catenin stabilizing mutations in a large series of parathyroid adenomas. A total of one hundred and eighty sporadic parathyroid adenomas were examined for mutations in exon 3 of the CTNNB1gene. The mutation S33C (TCT >TGT) was detected by direct-DNA sequencing of PCR fragments in 1 out of 180 sporadic parathyroid adenomas (0.68 %).

Eight matched tumor-constitutional DNA pairs from patients with sporadic parathyroid adenomas underwent whole-exome capture and high-throughput sequencing.  Four of eight tumors displayed a frame shift deletion or nonsense mutations within the MEN1 gene, which was accompanied by loss of heterozygosity of the remaining wild-type allele.  One tumor harbored a Y641N mutation of the histone methyltransferase EZH2 gene, previously linked to myeloid and lymphoid malignancy formation. Targeted sequencing in the additional 185 parathyroid adenomas revealed a high rate of MEN1 mutations (35%).

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2013. 36 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 927
Keyword
Parathyroid, yumorigenesis, mutation, exome sequencing
National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-205587 (URN)978-91-554-8727-0 (ISBN)
Public defence
2013-10-03, Rosen salen, Akademiska sjukhuset, ingång 95, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2013-09-10 Created: 2013-08-20 Last updated: 2014-01-22

Open Access in DiVA

No full text

Other links

Publisher's full text

Authority records BETA

Starker, Lee F.Åkerstom, GöranBjörklund, PeymanWestin, Gunnar

Search in DiVA

By author/editor
Starker, Lee F.Åkerstom, GöranBjörklund, PeymanWestin, Gunnar
By organisation
Experimental SurgeryDepartment of Surgical Sciences
In the same journal
Endocrine (Basingstoke)
Medical and Health Sciences

Search outside of DiVA

GoogleGoogle Scholar

doi
urn-nbn

Altmetric score

doi
urn-nbn
Total: 528 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf