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- Bausch, Birke, et al.
(author)
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Germline NF1 mutational spectra and loss-of-heterozygosity analyses in patients with pheochromocytoma and neurofibromatosis type 1.
- 2007
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In: Journal of Clinical Endocrinology and Metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 92:7, s. 2784-92
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Journal article (peer-reviewed)abstract
- BACKGROUND: Neurofibromatosis type 1 (NF1) is a pheochromocytoma-associated syndrome. Because of the low prevalence of pheochromocytoma in NF1, we ascertained subjects by pheochromocytoma that also had NF1 in the hope of describing the germline NF1 mutational spectra of NF1-related pheochromocytoma.MATERIALS AND METHODS: An international registry for NF1-pheochromocytomas was established. Mutation scanning was performed using denaturing HPLC for intragenic variation and quantitative PCR for large deletions. Loss-of-heterozygosity analysis using markers in and around NF1 was performed.RESULTS: There were 37 eligible subjects (ages 14-70 yr). Of 21 patients with corresponding tumor available, 67% showed somatic loss of the nonmutated allele at the NF1 locus vs. 0 of 12 sporadic tumors (P = 0.0002). Overall, 86% of the 37 patients had exonic or splice site mutations, 14% large deletions or duplications; 79% of the mutations are novel. The cysteine-serine rich domain (CSR) was affected in 35% but the RAS GTPase activating protein domain (RGD) in only 13%. There did not appear to be an association between any clinical features, particularly pheochromocytoma presentation and severity, and NF1 mutation genotype.CONCLUSIONS: The germline NF1 mutational spectra comprise intragenic mutations and deletions in individuals with pheochromocytoma and NF1. NF1 mutations tended to cluster in the CSR over the RAS-GAP domain, suggesting that CSR plays a more prominent role in individuals with NF1-pheochromocytoma than in NF1 individuals without this tumor. Loss-of-heterozygosity of NF1 markers in NF1-related pheochromocytoma was significantly more frequent than in sporadic pheochromocytoma, providing further molecular evidence that pheochromocytoma is a true component of NF1.
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| 2. |
- Barazeghi, Elham, et al.
(author)
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5-Hydroxymethylcytosine discriminates between parathyroid adenoma and carcinoma
- 2016
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In: Clinical Epigenetics. - : Springer Science and Business Media LLC. - 1868-7083 .- 1868-7075. ; 8
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Journal article (peer-reviewed)abstract
- Background: Primary hyperparathyroidism is characterized by enlarged parathyroid glands due to an adenoma (80-85 %) or multiglandular disease (similar to 15 %) causing hypersecretion of parathyroid hormone (PTH) and generally hypercalcemia. Parathyroid cancer is rare (<1-5 %). The epigenetic mark 5-hydroxymethylcytosine (5hmC) is reduced in various cancers, and this may involve reduced expression of the ten-eleven translocation 1 (TET1) enzyme. Here, we have performed novel experiments to determine the 5hmC level and TET1 protein expression in 43 parathyroid adenomas (PAs) and 17 parathyroid carcinomas (PCs) from patients who had local invasion or metastases and to address a potential growth regulatory role of TET1. Results: The global 5hmC level was determined by a semi-quantitative DNA immune-dot blot assay in a smaller number of tumors. The global 5hmC level was reduced in nine PCs and 15 PAs compared to four normal tissue samples (p < 0.05), and it was most severely reduced in the PCs. By immunohistochemistry, all 17 PCs stained negatively for 5hmC and TET1 showed negative or variably heterogeneous staining for the majority. All 43 PAs displayed positive 5hmC staining, and a similar aberrant staining pattern of 5hmC and TET1 was seen in about half of the PAs. Western blotting analysis of two PCs and nine PAs showed variable TET1 protein expression levels. A significantly higher tumor weight was associated to PAs displaying a more severe aberrant staining pattern of 5hmC and TET1. Overexpression of TET1 in a colony forming assay inhibited parathyroid tumor cell growth. Conclusions: 5hmC can discriminate between PAs and PCs. Whether 5hmC represents a novel marker for malignancy warrants further analysis in additional parathyroid tumor cohorts. The results support a growth regulatory role of TET1 in parathyroid tissue.
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| 3. |
- Barazeghi, Elham, et al.
(author)
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A role for TET2 in parathyroid carcinoma
- 2017
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In: Endocrine-Related Cancer. - 1351-0088 .- 1479-6821. ; 24:7, s. 329-338
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Journal article (peer-reviewed)abstract
- Primary hyperparathyroidism (pHPT) is rarely caused by parathyroid carcinoma (PC, <1-5% of pHPT cases). The TET proteins oxidize the epigenetic mark 5-methylcytosine to 5-hydroxymethylcytosine (5hmC) and inactivation by mutation or epigenetic deregulation of TET1 and TET2 play important roles in various cancers. Recently, we found that 5hmC was severely reduced in all of the analyzed PCs and with deranged expression of TET1 for the majority of PCs. Here, we have examined the expression of the TET2 protein in 15 5hmC-negative PCs from patients who had local invasion or metastases. Cell growth and cell migratory roles for TET2 as well as epigenetic deregulated expression were addressed. Immunohistochemistry revealed very low/undetectable expression of TET2 in all PCs and verified for two PCs that were available for western blotting analysis. Knockdown of TET2 in the parathyroid cell line sHPT-1 resulted in increased cell growth and increased cell migration. DNA sequencing of TET2 in PCs revealed two common variants and no obvious inactivating mutations. Quantitative bisulfite pyrosequencing analysis of the TET2 promoter CpG island revealed higher CpG methylation level in the PCs compared to that in normal tissues and treatment of a PC primary cell culture with the DNA methylation inhibitor 5-aza-2'-deoxycytidine caused increased expression of the methylated TET2 gene. Hence, the data suggest that deregulated expression of TET2 by DNA hypermethylation may contribute to the aberrantly low level of 5hmC in PCs and further that TET2 plays a cell growth and cell migratory regulatory role and may constitute a parathyroid tumor suppressor gene.
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| 4. |
- Vatansever, Safa, et al.
(author)
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Robot-assisted versus conventional laparoscopic adrenalectomy : Results from the EUROCRINE Surgical Registry
- 2022
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In: Surgery (United States). - : Elsevier BV. - 0039-6060. ; 171:5, s. 1224-1230
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Journal article (peer-reviewed)abstract
- Background: Adrenalectomy is routinely performed via the minimally invasive approach. Safety of adrenalectomy using the robot-assisted technique has been widely demonstrated by several series, but the literature is scarce regarding the comparison of conventional laparoscopic versus robot-assisted approach. We decided to carry out a multicenter study to compare clinical and surgical outcomes between laparoscopic and robotic adrenalectomy. Methods: This is a retrospective case-control study, including data from centers affiliated to the Surgical Registry EUROCRINE. Patients undergoing laparoscopic surgery for adrenal tumors and registered between 2015 and 2018 were included. Robot-assisted versus laparoscopic adrenalectomy was compared. All comparisons were carried out in terms of complication rate, conversion rate and duration of stay. Results: A total of 1,005 patients from 46 clinics underwent robotic or conventional laparoscopic adrenalectomy. Median age was 55 (interquartile range: 45−65) years. Robotic adrenalectomy was performed in 189 (18.8%) patients. According to Clavien-Dindo classification, complication rate was lower in the robotic surgery group (1.6% vs 16.5%, P <.001). Laparoscopic surgery and active hormonal status were significantly correlated with complications, both in univariate and multivariate analysis. There was no significant difference between laparoscopic and robotic surgery groups, in terms of conversion rate (2.1% vs 0.5%, respectively, P =.147). Duration of stay was shorter in the robotic adrenalectomy group (82.1% vs 28.8%, P <.001). Conclusion: Analysis of the EUROCRINE database supports that robotic adrenalectomy resulted in a lower complication rate and shorter duration of stay, compared with laparoscopic adrenalectomy. Granular data to support this is warranted.
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