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Frequent germ-line mutations of the MEN1, CASR, and HRPT2/CDC73 genes in young patients with clinically non-familial primary hyperparathyroidism
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, Experimental Surgery.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Experimental Surgery.
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2012 (English)In: Hormones & Cancer, ISSN 1868-8497, Vol. 3, no 1-2, 44-51 p.Article in journal (Refereed) Published
Abstract [en]

Familial primary hyperparathyroidism (FPHPT) may occur due to an underlying germ-line mutation in the MEN1, CASR, or HRPT2/CDC73 genes. The disease may be undiagnosed in the absence of a history suggestive of FHPT. Young PHPT patients (≤45 years of age) are more likely to harbor occult FPHPT. A total of 1,161 (136 were ≤45 years of age) PHPT patients underwent parathyroidectomy from 2001 to 2009. Thirty-four patients declined participation. Sixteen patients were diagnosed in the clinical routine with FPHPT (11 MEN1, four MEN2A, and one HPT-JT) and were not included in the genetic analysis. Eighty-six young (≤45 years of age) patients with clinically non-syndromic PHPT underwent genetic analysis. Sanger sequencing of all coding regions of the MEN1, CASR, and the HRPT2/CDC73 genes was performed. 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). There was one insertion, one deletion, two nonsense, and four missense mutations, all predicted to be highly damaging to protein function and absent in 3,244 control chromosomes. Germ-line mutations in known susceptibility genes within young patients with PHPT, including those diagnosed in the clinical routine, was 24/102 (23.5%; 15 MEN1, four RET, three CASR, and two HRPT2/CDC73). We demonstrate that germ-line inactivating mutations in susceptibility genes are common in young patients with clinically non-familial PHPT. Thus, enhanced use of genetic analysis may be warranted in clinically non-familial young PHPT patients.

Place, publisher, year, edition, pages
2012. Vol. 3, no 1-2, 44-51 p.
National Category
Medical Genetics
Identifiers
URN: urn:nbn:se:uu:diva-205584DOI: 10.1007/s12672-011-0100-8PubMedID: 22187299OAI: oai:DiVA.org:uu-205584DiVA: diva2:642095
Available from: 2013-08-20 Created: 2013-08-20 Last updated: 2016-12-21Bibliographically approved
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)
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Supervisors
Available from: 2013-09-10 Created: 2013-08-20 Last updated: 2014-01-22

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Starker, Lee F.Delgado-Verdugo, Alberto

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