| 1. |
- Åkerström, Tobias, et al.
(författare)
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Comprehensive Re-Sequencing of Adrenal Aldosterone Producing Lesions Reveal Three Somatic Mutations near the KCNJ5 Potassium Channel Selectivity Filter.
- 2012
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Ingår i: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 7:7
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Tidskriftsartikel (refereegranskat)abstract
- Aldosterone producing lesions are a common cause of hypertension, but genetic alterations for tumorigenesis have been unclear. Recently, either of two recurrent somatic missense mutations (G151R or L168R) was found in the potassium channel KCNJ5 gene in aldosterone producing adenomas. These mutations alter the channel selectivity filter and result in Na(+) conductance and cell depolarization, stimulating aldosterone production and cell proliferation. Because a similar mutation occurs in a Mendelian form of primary aldosteronism, these mutations appear to be sufficient for cell proliferation and aldosterone production. The prevalence and spectrum of KCNJ5 mutations in different entities of adrenocortical lesions remain to be defined.
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| 2. |
- Crona, Joakim, et al.
(författare)
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Somatic Mutations and Genetic Heterogeneity at the CDKN1B Locus in Small Intestinal Neuroendocrine Tumors
- 2015
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Ingår i: Annals of Surgical Oncology. - : Springer Science and Business Media LLC. - 1068-9265 .- 1534-4681. ; 22, s. 1428-1435
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Until recently, the genetic landscape of small intestinal neuroendocrine tumors (SI-NETs) was limited to recurrent copy number alterations, most commonly a loss on chromosome 18. Intertumor heterogeneity with nonconcordant genotype in paired primary and metastatic lesions also is described, further contributing to the difficulty of unraveling the genetic enigma of SI-NETs. A recent study analyzing 55 SI-NET exomes nominated CDKN1B (p27) as a haploinsufficient tumor suppressor gene.METHODS: This study aimed to determine the frequency of CDKN1B inactivation and to investigate genotype-phenotype correlations. It investigated 362 tumors from 200 patients. All samples were resequenced for mutations in CDKN1B using automated Sanger sequencing. The expression of p27 was investigated in 12 CDKN1B mutant and nine wild type tumors.RESULTS: Some 8.5 % (17/200) of patients had tumors with pathogenic mutations in CDKN1B including 13 insertion deletions, four nonsense variants, and one stop-loss variant. All variants with available nontumoral DNA were classified as somatic. Inter- and intratumor heterogeneity at the CDKN1B locus was detected respectively in six of ten and two of ten patients. Patients with CDKN1B mutated tumors had both heterogeneous disease presentation and diverse prognosis. Expression of the p27 protein did not correlate with CDKN1B mutation status, and no differences in the clinical characteristics between CDKN1B mutated and CDKN1B wild type tumor carriers were found.CONCLUSION: This study corroborates the finding of CDKN1B as a potential haplo-insufficient tumor suppressor gene characterized by inter- and intratumor heterogeneity in SI-NETs.
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| 3. |
- Starker, Lee F., et al.
(författare)
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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
- 2012
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Ingår i: Hormones & Cancer. - : Springer Science and Business Media LLC. - 1868-8497 .- 1868-8500. ; 3:1-2, s. 44-51
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 4. |
- Backman, Samuel, et al.
(författare)
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RNA Sequencing Provides Novel Insights into the Transcriptome of Aldosterone Producing Adenomas
- 2019
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Ingår i: Scientific Reports. - : NATURE PUBLISHING GROUP. - 2045-2322. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Aldosterone producing adenomas (APAs) occur in the adrenal glands of around 30% of patients with primary aldosteronism, the most common form of secondary hypertension. Somatic mutations in KCNJ5, ATP1A1, ATP2B3, CACNA1D and CTNNB1 have been described in similar to 60% of these tumours. We subjected 15 aldosterone producing adenomas (13 with known mutations and two without) to RNA Sequencing and Whole Genome Sequencing (n = 2). All known mutations were detected in the RNA-Seq reads, and mutations in ATP2B3 (G123R) and CACNA1D (S410L) were discovered in the tumours without known mutations. Adenomas with CTNNB1 mutations showed a large number of differentially expressed genes (1360 compared to 106 and 75 for KCNJ5 and ATP1A1/ATP2B3 respectively) and clustered together in a hierarchical clustering analysis. RT-PCR in an extended cohort of 49 APAs confirmed higher expression of AFF3 and ISM1 in APAs with CTNNB1 mutations. Investigation of the expression of genes involved in proliferation and apoptosis revealed subtle differences between tumours with and without CTNNB1 mutations. Together our results consolidate the notion that CTNNB1 mutations characterize a distinct subgroup of APAs.
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| 5. |
- Backman, Samuel, et al.
(författare)
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The Evolutionary History of Metastatic Pancreatic Neuroendocrine Tumours Reveals a Therapy Driven Route to High-Grade Transformation.
- 2024
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Ingår i: medRxiv : the preprint server for health sciences.
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Tidskriftsartikel (refereegranskat)abstract
- Tumour evolution with acquisition of more aggressive disease characteristics is a hallmark of disseminated cancer. Metastatic pancreatic neuroendocrine tumours (PanNETs) in particular, show frequent progression from a low/intermediate to a high-grade disease. To understand the molecular mechanisms underlying this phenomenon, we performed multi-omics analysis of 32 longitudinal samples from six metastatic PanNET patients. Following MEN1 inactivation, PanNETs exhibit genetic heterogeneity on both spatial and temporal dimensions with parallel and convergent tumuor evolution involving the ATRX/DAXX and mTOR pathways. Following alkylating chemotherapy treatment, some PanNETs develop mismatch repair deficiency and acquire a hypermutator phenotype. This DNA hypermutation phenotype was only found in cases that also showed transformation into a high-grade PanNET. Overall, our findings contribute to broaden the understanding of metastatic PanNET, and suggests that therapy driven disease evolution is an important hallmark of this disease.
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| 6. |
- Björklund, Peyman, et al.
(författare)
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Type I membrane Klotho expression is decreased and inversely correlated to serum calcium in primary hyperparathyroidism
- 2008
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Ingår i: Journal of Clinical Endocrinology and Metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 93:10, s. 4152-4157
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Tidskriftsartikel (refereegranskat)abstract
- Context: The type I membrane protein Klotho was recently shownto mediate PTH secretion in parathyroid cells in response tolow extracellular calcium. In contrast, Klotho inhibits PTHsecretion indirectly through the action of fibroblast growthfactor-23. Abnormal Klotho expression in parathyroid disordersremains to be elucidated.Objective: The aim of the study was to determine: 1) Klothoexpression in parathyroid adenomas from patients with primaryhyperparathyroidism (pHPT) compared to normal tissue; and 2)its relation to the serum calcium and PTH levels.Design: Surgically removed parathyroid glands (n = 40) and fournormal parathyroid tissue specimens were analyzed for KlothomRNA and protein levels by quantitative real-time PCR and immunohistochemistry.In vitro effects of calcium on Klotho mRNA expression were studiedin bovine parathyroid cells.Results: Klotho mRNA levels were significantly decreased (n= 23) or undetectable (n = 17) in parathyroid adenomas comparedto normal tissues (P < 0.001). Reduced Klotho protein expressionwas confirmed by immunohistochemistry. Klotho mRNA levels wereinversely correlated to serum calcium (r = –0.97; P <0.0001), and calcium dose-dependently decreased Klotho mRNAexpression in normal parathyroid cells in vitro (P < 0.01).Serum calcium was the only significant marker of Klotho expressionin multivariate analysis with calcium, phosphate, PTH, and adenomaweight as independent variables.Conclusions: Parathyroid Klotho expression is decreased or undetectablein pHPT. We provide evidence that 1) serum calcium is stronglyassociated with parathyroid Klotho expression in pHPT; and 2)abnormal PTH secretion in hypercalcemic pHPT subjects is mediatedby Klotho-independent mechanisms.
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| 7. |
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| 8. |
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| 9. |
- Carling, Tobias, et al.
(författare)
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Hyperparathyroidism of multiple endocrine neoplasia type 1 : candidate gene and parathyroid calcium sensing protein expression
- 1995
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Ingår i: Surgery. - 0039-6060 .- 1532-7361. ; 118:6, s. 924-931
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND:Hyperparathyroidism affects most patients with multiple endocrine neoplasia type 1 (MEN 1). This study investigates expression of the candidate MEN1 gene phospholipase C beta 3 (PLC beta 3) and expression and function of a putative calcium sensing protein (CAS) in hyperparathyroidism of MEN 1.METHODS:In 31 parathyroid glands from 17 patients with MEN 1, CAS distribution was studied immunohistochemically and parallel sections were explored for PLC beta 3 mRNA expression by in situ hybridization. Enzymatically dispersed parathyroid cells were analyzed for cytoplasmic calcium concentrations [Ca2+]i and parathyroid hormone (PTH) release.RESULTS:All glands exhibited a heterogeneously reduced CAS immunoreactivity, especially meager in nodularly assembled parathyroid cells. Calcium regulated [Ca2+]i and PTH release tended to be more deranged in the glands possessing the lowest immunostaining. Parathyroid PLC beta 3 invariably was homogeneously expressed, and this included even MEN 1 patients with reduced PLC beta 3 expression in endocrine pancreatic tumors.CONCLUSIONS:The findings support variable calcium insensitivity of [Ca2+]i and PTH release in hyperparathyroidism of MEN 1, apparently coupled to heterogeneously reduced CAS expression. For clarification of the role of PLC beta 3 in MEN 1 parathyroid tumorigenesis further study of this protein is required.
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| 10. |
- Carling, Tobias, et al.
(författare)
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Parathyroid MEN 1 gene mutations in relation to clinical characteristics of non-familial primary hyperparathyroidism
- 1998
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Ingår i: Journal of Clinical Endocrinology and Metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 83:8, s. 2960-2963
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Tidskriftsartikel (refereegranskat)abstract
- Biochemical signs and severity of symptoms of primary hyperparathyroidism (pHPT) differ among patients, and little is known of any coupling of clinical characteristics of nonfamilial pHPT to genetic abnormalities in the parathyroid tumors. Mutations in the recently identified MEN1 gene at chromosome 11q13 have been found in parathyroid tumors of nonfamilial pHPT. Using microsatellite analysis for loss of heterozygosity (LOH) at 11q13 and DNA sequencing of coding exons, the MEN1 gene was studied in 49 parathyroid lesions of patients with divergent symptoms, operative findings, histopathological diagnosis, and biochemical signs of nonfamilial pHPT. Allelic loss at 11q13 was detected in 13 tumors, and 6 of them demonstrated previously unrecognized somatic missense and frameshift deletion mutations of the MEN1 gene. Many of the detected mutations would most likely result in a nonfunctional menin protein, consistent with a tumor suppressor mechanism. Clinical and biochemical characteristics of HPT were apparently unrelated to the presence or absence of LOH and the MEN1 gene mutations. However, the demonstration of LOH at 11q13 and MEN1 gene mutations in small parathyroid adenomas of patients with slight hypercalcemia and normal serum PTH levels suggest that altered MEN1 gene function may also be important for the development of mild sporadic pHPT.
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