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- Björklund, Peyman, et al.
(författare)
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Stabilizing mutation of CTNNB1/beta-catenin and protein accumulation analyzed in a large series of parathyroid tumors of Swedish patients
- 2008
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Ingår i: Molecular Cancer. - : Springer Science and Business Media LLC. - 1476-4598. ; 7, s. 53-
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Aberrant accumulation of beta-catenin plays an important role in a variety of human neoplasms. We recently reported accumulation of beta-catenin in parathyroid adenomas from patients with primary hyperparathyroidism (pHPT). In CTNNB1 exon 3, we detected a stabilizing mutation (S37A) in 3 out of 20 analyzed adenomas. The aim of the present study was to determine the frequency and zygosity of mutations in CTNNB1 exon 3, and beta-catenin accumulation in a large series of parathyroid adenomas of Swedish patients. RESULTS: The mutation S37A (TCT > GCT) was detected by direct DNA sequencing of PCR fragments in 6 out of 104 sporadic parathyroid adenomas (5.8%). Taking our previous study into account, a total of 9 out of 124 (7.3%) adenomas displayed the same mutation. The mutations were homozygous by DNA sequencing, restriction enzyme cleavage, and gene copy number determination using the GeneChip 500 K Mapping Array Set. All tumors analyzed by immunohistochemistry, including those with mutation, displayed aberrant beta-catenin accumulation. Western blotting revealed a slightly higher expression level of beta-catenin and nonphosphorylated active beta-catenin in tumors with mutation compared to those without. Presence of the mutation was not related to distinct clinical characteristics. CONCLUSION: Aberrant accumulation of beta-catenin is very common in parathyroid tumors, and is caused by stabilizing homozygous mutation in 7.3% of Swedish pHPT patients.
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| 2. |
- Svedlund, Jessica, et al.
(författare)
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Aberrant WNT/beta-catenin signaling in parathyroid carcinoma
- 2010
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Ingår i: Molecular Cancer. - : Springer Science and Business Media LLC. - 1476-4598. ; 9, s. 294-
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Tidskriftsartikel (refereegranskat)abstract
- Background: Parathyroid carcinoma (PC) is a very rare malignancy with a high tendency to recur locally, and recurrent disease is difficult to eradicate. In most western European countries and United States, these malignant neoplasms cause less than 1% of the cases with primary hyperparathyroidism, whereas incidence as high as 5% have been reported from Italy, Japan, and India. The molecular etiology of PC is poorly understood. Results: The APC (adenomatous polyposis coli) tumor suppressor gene was inactivated by DNA methylation in five analyzed PCs, as determined by RT-PCR, Western blotting, and quantitative bisulfite pyrosequencing analyses. This was accompanied by accumulation of stabilized active nonphosphorylated beta-catenin, strongly suggesting aberrant activation of the WNT/beta-catenin signaling pathway in these tumors. Treatment of a primary PC cell culture with the DNA hypomethylating agent 5-aza-2'-deoxycytidine (decitabine, Dacogen(r)) induced APC expression, reduced active nonphosphorylated beta-catenin, inhibited cell growth, and caused apoptosis. Conclusion: Aberrant WNT/beta-catenin signaling by lost expression and DNA methylation of APC, and accumulation of active nonphosphorylated beta-catenin was observed in the analyzed PCs. We suggest that adjuvant epigenetic therapy should be considered as an additional option in the treatment of patients with recurrent or metastatic parathyroid carcinoma.
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