| 11. |
- Fonseca, Annabelle L, et al.
(författare)
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Comprehensive DNA methylation analysis of benign and malignant adrenocortical tumors
- 2012
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Ingår i: Genes, Chromosomes and Cancer. - : Wiley-Blackwell. - 1045-2257 .- 1098-2264. ; 51:10, s. 949-960
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Tidskriftsartikel (refereegranskat)abstract
- The molecular pathogenesis of benign and malignant adrenocortical tumors (ACT) is incompletely clarified. The role of DNA methylation in adrenocortical tumorigenesis has not been analyzed in an unbiased, systematic fashion. Using the Infinium HumanMethylation27 BeadChip, the DNA methylation levels of 27,578 CpG sites were investigated in bisulfite-modified DNA from 6 normal adrenocortical tissue samples, 27 adrenocortical adenomas (ACA), and 15 adrenocortical carcinomas (ACC). Genes involved in cell cycle regulation, apoptosis, and transcriptional regulation of known or putative importance in the development of adrenal tumors showed significant and frequent hypermethylation. Such genes included CDKN2A, GATA4, BCL2, DLEC1, HDAC10, PYCARD, and SCGB3A1/HIN1. Comparing benign versus malignant ACT, a total of 212 CpG islands were identified as significantly hypermethylated in ACC. Gene expression studies of selected hypermethylated genes (CDKN2A, GATA4, DLEC1, HDAC10, PYCARD, SCGB3A1/HIN1) in 6 normal and 16 neoplastic adrenocortical tissues (10 ACA and 6 ACC), displayed reduced gene expression in benign and malignant ACT versus normal adrenocortical tissue. Treatment with 5-aza-2-deoxycytidine of adrenocortical cancer H-295R cells increased expression of the hypermethylated genes CDKN2A, GATA4, DLEC1, HDAC10, PYCARD, and SCGB3A1/HIN1. In conclusion, the current study represents the first unbiased, quantitative, genome-wide study of adrenocortical tumor DNA methylation. Genes with altered DNA methylation patterns were identified of putative importance to benign and malignant adrenocortical tumor development.
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| 12. |
- Goh, Gerald, et al.
(författare)
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Recurrent activating mutation in PRKACA in cortisol-producing adrenal tumors
- 2014
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 46:6, s. 613-617
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Tidskriftsartikel (refereegranskat)abstract
- Adrenal tumors autonomously producing cortisol cause Cushing's syndrome1, 2, 3, 4. We performed exome sequencing of 25 tumor-normal pairs and identified 2 subgroups. Eight tumors (including three carcinomas) had many somatic copy number variants (CNVs) with frequent deletion of CDC42 and CDKN2A, amplification of 5q31.2 and protein-altering mutations in TP53 and RB1. Seventeen tumors (all adenomas) had no somatic CNVs or TP53 or RB1 mutations. Six of these had known gain-of-function mutations in CTNNB1 (β-catenin)5, 6 or GNAS (Gαs)7, 8. Six others had somatic mutations in PRKACA (protein kinase A (PKA) catalytic subunit) resulting in a p.Leu206Arg substitution. Further sequencing identified this mutation in 13 of 63 tumors (35% of adenomas with overt Cushing's syndrome). PRKACA, GNAS and CTNNB1 mutations were mutually exclusive. Leu206 directly interacts with the regulatory subunit of PKA, PRKAR1A9, 10. Leu206Arg PRKACA loses PRKAR1A binding, increasing the phosphorylation of downstream targets. PKA activity induces cortisol production and cell proliferation11, 12, 13, 14, 15, providing a mechanism for tumor development. These findings define distinct mechanisms underlying adrenal cortisol-producing tumors.
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| 13. |
- Leu, Monica, et al.
(författare)
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NordicDB : a Nordic pool and portal for genome-wide control data
- 2010
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Ingår i: European Journal of Human Genetics. - : Springer Science and Business Media LLC. - 1018-4813 .- 1476-5438. ; 18:12, s. 1322-1326
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Tidskriftsartikel (refereegranskat)abstract
- A cost-efficient way to increase power in a genetic association study is to pool controls from different sources. The genotyping effort can then be directed to large case series. The Nordic Control database, NordicDB, has been set up as a unique resource in the Nordic area and the data are available for authorized users through the web portal (http://www.nordicdb.org). The current version of NordicDB pools together high-density genome-wide SNP information from similar to 5000 controls originating from Finnish, Swedish and Danish studies and shows country-specific allele frequencies for SNP markers. The genetic homogeneity of the samples was investigated using multidimensional scaling (MDS) analysis and pairwise allele frequency differences between the studies. The plot of the first two MDS components showed excellent resemblance to the geographical placement of the samples, with a clear NW-SE gradient. We advise researchers to assess the impact of population structure when incorporating NordicDB controls in association studies. This harmonized Nordic database presents a unique genome-wide resource for future genetic association studies in the Nordic countries. European Journal of Human Genetics (2010) 18, 1322-1326; doi: 10.1038/ejhg.2010.112; published online 28 July 2010
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| 14. |
- Lifton, Nathaniel, et al.
(författare)
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Constraints on the late Quaternary glacial history of the Inylchek and Sary-Dzaz valleys from in situ cosmogenic Be-10 and Al-26, eastern Kyrgyz Tian Shan
- 2014
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Ingår i: Quaternary Science Reviews. - : Elsevier BV. - 0277-3791 .- 1873-457X. ; 101, s. 77-90
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Tidskriftsartikel (refereegranskat)abstract
- Paleoclimatic constraints from regions at the confluence of major climate systems are particularly important in understanding past climate change. Using geomorphic mapping based on remote sensing and field investigations, combined with in situ cosmogenic Be-10 and Al-26 dating of boulders associated with glacial landforms, we investigate the chronology of past glaciation in the Inylchek and Sary-Dzaz valleys in the eastern Kyrgyz Tian Shan, a tectonically active area with some of the highest peaks in the world outside of the Himalayas. Cosmogenic Be-10 and (26) Al exposure ages of boulders on moraines record up to five glacial advances including: Lateglacial age lateral moraine remnants and meltwater channels in the upper Inylchek Valley; Last Glacial Maximum (LGM, Marine Oxygen Isotope Stage [MIS] 2) moraines in the Sary-Dzaz Valley and in a terminal moraine complex at the west end of the Inylchek Valley, overriding older moraines; an MIS 4 or 5 moraine remnant above the Inylchek terminal moraine complex; and an older high moraine remnant down-valley from the confluence of the Inylchek and Sary-Dzaz valleys. The evidence for glacial extent in this study is consistent with a limited ice expansion hypothesis for Tian Shan glaciation. Published results from the western and central Kyrgyz Tian Shan do not show evidence for significant LGM glacier expansion, which in combination with the results presented here, indicate a spatial variation in glacier records along the Tian Shan. This may reflect either paleoclimatic gradients or the impact of local physiographic conditions on responses to regional climate change, or both.
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| 15. |
- Mas e Braga, Martim, et al.
(författare)
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Antarctic ice stream thickening under Pliocene warmth
- 2024
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Ice streams regulate most ice mass loss in Antarctica. Determining their response to Pliocene warmth could provide insights into their future behaviour, but is hindered by poor representation of subglacial topography in ice-sheet models. We address this limitation using a high-resolution regional model for Dronning Maud Land (East Antarctica). We show that the region’s largest ice stream, Jutulstraumen, thickens by 700 m under warm late-Pliocene conditions despite ice-shelf collapse and a retrograde bed slope, while nearby ice streams thin. While it is known that unstable retreat on a retrograde slope can be slowed under certain conditions, this finding illustrates that an ice stream can thicken and gain mass. We attribute thickening to high lateral stresses at its flux gate, which constrict ice drainage. Similar stress balances occur today in 27% of East Antarctica, and understanding how lateral stresses regulate ice-stream discharge is necessary for accurately assessing Antarctica’s sea-level rise contribution.
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| 16. |
- Mas e Braga, Martim, et al.
(författare)
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Nunataks as barriers to ice flow : implications for palaeo ice sheet reconstructions
- 2021
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Ingår i: The Cryosphere. - : Copernicus GmbH. - 1994-0416 .- 1994-0424. ; 15:10, s. 4929-4947
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Tidskriftsartikel (refereegranskat)abstract
- Numerical models predict that discharge from the polar ice sheets will become the largest contributor to sea-level rise over the coming centuries. However, the predicted amount of ice discharge and associated thinning depends on how well ice sheet models reproduce glaciological processes, such as ice flow in regions of large topographic relief, where ice flows around bedrock summits (i.e. nunataks) and through outlet glaciers. The ability of ice sheet models to capture long-term ice loss is best tested by comparing model simulations against geological data. A benchmark for such models is ice surface elevation change, which has been constrained empirically at nunataks and along margins of outlet glaciers using cosmogenic exposure dating. However, the usefulness of this approach in quantifying ice sheet thinning relies on how well such records represent changes in regional ice surface elevation. Here we examine how ice surface elevations respond to the presence of strong topographic relief that acts as an obstacle by modelling ice flow around and between idealised nunataks during periods of imposed ice sheet thinning. We find that, for realistic Antarctic conditions, a single nunatak can exert an impact on ice thickness over 20 km away from its summit, with its most prominent effect being a local increase (decrease) of the ice surface elevation of hundreds of metres upstream (downstream) of the obstacle. A direct consequence of this differential surface response for cosmogenic exposure dating is a delay in the time of bedrock exposure upstream relative to downstream of a nunatak summit. A nunatak elongated transversely to ice flow is able to increase ice retention and therefore impose steeper ice surface gradients, while efficient ice drainage through outlet glaciers produces gentler gradients. Such differences, however, are not typically captured by continent-wide ice sheet models due to their coarse grid resolutions. Their inability to capture site-specific surface elevation changes appears to be a key reason for the observed mismatches between the timing of ice-free conditions from cosmogenic exposure dating and model simulations. We conclude that a model grid refinement over complex topography and information about sample position relative to ice flow near the nunatak are necessary to improve data-model comparisons of ice surface elevation and therefore the ability of models to simulate ice discharge in regions of large topographic relief.
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| 17. |
- Matuozzo, Daniela, et al.
(författare)
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Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19.
- 2023
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Ingår i: Genome medicine. - 1756-994X. ; 15:1
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Tidskriftsartikel (refereegranskat)abstract
- We previously reported that impaired type I IFN activity, due to inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity or to autoantibodies against type I IFN, account for 15-20% of cases of life-threatening COVID-19 in unvaccinated patients. Therefore, the determinants of life-threatening COVID-19 remain to be identified in~80% of cases.We report here a genome-wide rare variant burden association analysis in 3269 unvaccinated patients with life-threatening COVID-19, and 1373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. Among the 928 patients tested for autoantibodies against type I IFN, a quarter (234) were positive and were excluded.No gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants was TLR7, with an OR of 27.68 (95%CI 1.5-528.7, P=1.1×10-4) for biochemically loss-of-function (bLOF) variants. We replicated the enrichment in rare predicted LOF (pLOF) variants at 13 influenza susceptibility loci involved in TLR3-dependent type I IFN immunity (OR=3.70[95%CI 1.3-8.2], P=2.1×10-4). This enrichment was further strengthened by (1) adding the recently reported TYK2 and TLR7 COVID-19 loci, particularly under a recessive model (OR=19.65[95%CI 2.1-2635.4], P=3.4×10-3), and (2) considering as pLOF branchpoint variants with potentially strong impacts on splicing among the 15 loci (OR=4.40[9%CI 2.3-8.4], P=7.7×10-8). Finally, the patients with pLOF/bLOF variants at these 15 loci were significantly younger (mean age [SD]=43.3 [20.3] years) than the other patients (56.0 [17.3] years; P=1.68×10-5).Rare variants of TLR3- and TLR7-dependent type I IFN immunity genes can underlie life-threatening COVID-19, particularly with recessive inheritance, in patients under 60years old.
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| 18. |
- Scholl, Ute I, et al.
(författare)
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Somatic and germline CACNA1D calcium channel mutations in aldosterone-producing adenomas and primary aldosteronism
- 2013
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:9, s. 1050-1054
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Tidskriftsartikel (refereegranskat)abstract
- Adrenal aldosterone-producing adenomas (APAs) constitutively produce the salt-retaining hormone aldosterone and are a common cause of severe hypertension. Recurrent mutations in the potassium channel gene KCNJ5 that result in cell depolarization and Ca2+ influx cause ~40% of these tumors1. We identified 5 somatic mutations (4 altering Gly403 and 1 altering Ile770) in CACNA1D, encoding a voltage-gated calcium channel, among 43 APAs without mutated KCNJ5. The altered residues lie in the S6 segments that line the channel pore. Both alterations result in channel activation at less depolarized potentials; Gly403 alterations also impair channel inactivation. These effects are inferred to cause increased Ca2+ influx, which is a sufficient stimulus for aldosterone production and cell proliferation in adrenal glomerulosa2. We also identified de novo germline mutations at identical positions in two children with a previously undescribed syndrome featuring primary aldosteronism and neuromuscular abnormalities. These findings implicate gain-of-function Ca2+ channel mutations in APAs and primary aldosteronism.
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| 19. |
- 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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| 20. |
- Starker, Lee F., et al.
(författare)
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The DNA Methylome of Benign and Malignant Parathyroid Tumors
- 2011
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Ingår i: Genes, Chromosomes and Cancer. - : Wiley. - 1045-2257 .- 1098-2264. ; 50:9, s. 735-745
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Tidskriftsartikel (refereegranskat)abstract
- The role of DNA methylation of CpG islands in parathyroid tumorigenesis has not been analyzed in an unbiased, systematic fashion. DNA was isolated from normal and pathologic parathyroid tissues, 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. Comparing normal parathyroid tissue with parathyroid adenomas, 367 genes were significantly altered, while 175 genes significantly differed when comparing parathyroid carcinomas and normal parathyroid tissues. A comparison between parathyroid adenomas and parathyroid carcinomas identified 263 genes with significantly distinct methylation levels. Results were confirmed for certain genes in a validation cohort of 40 parathyroid adenomas by methylation-specific PCR. Genes of known or putative importance in the development of parathyroid tumors showed significant and frequent hypermethylation. DNA hypermethylation of CDKN2B, CDKN2A, WT1, SFRP1, SFRP2, and SFRP4 was associated with reduced gene expression in both benign and malignant parathyroid tumors. Treatment with 5-aza-2 '-deoxycytidine of primary cell cultures restores expression of hypermethylated genes in benign and malignant parathyroid tumors. In conclusion, the unbiased, genome-wide study of the parathyroid tumor DNA methylome identified a number of genes with altered DNA methylation patterns of putative importance to benign and malignant parathyroid tumorigenesis.
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