Frequent aberrant DNA methylation of CDKN2A locus in capillary hemangioblastomas, pheochromocytomas and gliomas

Background. Both capillary hemangioblastoma (CHB) and pheochromocytoma (PCC) are rare, usually benign tumours occurring sporadically or as part of familial cancer syndromes. The genetic background of most of the inherited cases is well established, but the molecular causes of sporadic cases remains poorly characterized. To better understand the molecular mechanisms of CHB and PCC pathogenesis, we analysed the genetic and epigenetic alterations of the p16 and p14 genes at the CDKN2A locus. Materials and methods. Aberrant methylation of the p16 and p14 genes was analysed in 16 cases with CHB or PCC by means of methylation-specific PCR. The differential polymerase chain reaction was used to prove the occurrence of the genetic deletion of p16. For comparison, 28 cases of glioma – a highly malignant tumour of the brain – was included into the study. Results. Data of our study show that gene p16 is hypermethylated in 25% of CHBs and in 25% of PCCs, while in gliomas this alteration is more frequent (35%) and predominantly occurs in low-grade tumours (67%). Frequent hypermethylation of the p14 gene was observed in PCCs (50%) and CHBs (37.5%), but was less prevalent in gliomas (26%). When all alterations in the CDKN2A locus were considered, including hypermethylation of p16 and p14, and genetic deletion of p16, 75% of PCC, 62.5% of CHB, and 64% of gliomas had at least one alteration of this locus. Conclusions. Our study adds new data to understanding the involvement of the CDKN2A locus in the pathogenesis of CHB and PCC – two of the most common VHL-related tumours. Furthermore, aberrant methylation in the CDKN2A locus is also frequent in gliomas. Keywords: CDKN2A locus, promoter methylation, glioma, capillary hemangioblastoma, pheochromocytoma

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TET2 promoter methylation in low-grade diffuse gliomas lacking IDH1/2 mutations: Figure 1

Journal of Clinical Pathology ◽

10.1136/jclinpath-2011-200133 ◽

2011 ◽

Vol 64 (10) ◽

pp. 850-852 ◽

Cited By ~ 49

Author(s):

Young-Ho Kim ◽

Daniela Pierscianek ◽

Michel Mittelbronn ◽

Anne Vital ◽

Luigi Mariani ◽

...

Keyword(s):

Promoter Methylation ◽

Molecular Mechanisms ◽

Direct Sequencing ◽

Dna Demethylation ◽

Low Grade ◽

Alternative Mechanism ◽

Single Strand Conformational Polymorphism ◽

Specific Pcr ◽

Diffuse Gliomas ◽

Acute Myeloid

BackgroundMiscoding mutations of the TET2 gene, which encodes the α-ketoglutarate-dependent enzyme that catalyses the conversion of 5-methylcytosine to 5-hydroxymethylcytosine, thus producing DNA demethylation, have been detected in 10–25% of acute myeloid leukaemias lacking IDH1/2 mutations. Most low-grade diffuse gliomas carry IDH1/2 mutations (>85%), but molecular mechanisms of pathogenesis in those lacking IDH1/2 mutations remain to be elucidated.MethodsMiscoding mutations and promoter methylation of the TET2 gene were screened for in 29 low-grade diffuse gliomas lacking IDH1/2 mutations.ResultsSingle-strand conformational polymorphism followed by direct sequencing showed the absence of miscoding mutations in TET2. Methylation-specific PCR revealed methylation of the TET2 promoter in 5 of 35 cases (14%). In contrast, none of 38 low-grade diffuse gliomas with IDH1/2 mutations had TET2 promoter methylation (p=0.0216).ConclusionResults suggest that TET2 promoter methylation, but not TET2 mutation, may be an alternative mechanism of pathogenesis in a small fraction of low-grade diffuse gliomas lacking IDH1/2 mutations.

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Molecular Mechanisms of Alcohol-Induced Colorectal Carcinogenesis

Cancers ◽

10.3390/cancers13174404 ◽

2021 ◽

Vol 13 (17) ◽

pp. 4404

Author(s):

Caroline H. Johnson ◽

Jaya Prakash Golla ◽

Evangelos Dioletis ◽

Surendra Singh ◽

Momoko Ishii ◽

...

Keyword(s):

Molecular Mechanisms ◽

Familial Cancer ◽

Genotoxic Stress ◽

Redox Balance ◽

Colorectal Carcinogenesis ◽

Alcohol Metabolism ◽

Cellular Redox ◽

Familial Cancer Syndromes ◽

One Carbon Metabolism ◽

Cancer Syndromes

The etiology of colorectal cancer (CRC) is complex. Approximately, 10% of individuals with CRC have predisposing germline mutations that lead to familial cancer syndromes, whereas most CRC patients have sporadic cancer resulting from a combination of environmental and genetic risk factors. It has become increasingly clear that chronic alcohol consumption is associated with the development of sporadic CRC; however, the exact mechanisms by which alcohol contributes to colorectal carcinogenesis are largely unknown. Several proposed mechanisms from studies in CRC models suggest that alcohol metabolites and/or enzymes associated with alcohol metabolism alter cellular redox balance, cause DNA damage, and epigenetic dysregulation. In addition, alcohol metabolites can cause a dysbiotic colorectal microbiome and intestinal permeability, resulting in bacterial translocation, inflammation, and immunosuppression. All of these effects can increase the risk of developing CRC. This review aims to outline some of the most significant and recent findings on the mechanisms of alcohol in colorectal carcinogenesis. We examine the effect of alcohol on the generation of reactive oxygen species, the development of genotoxic stress, modulation of one-carbon metabolism, disruption of the microbiome, and immunosuppression.

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Inflammageing in the cardiovascular system: mechanisms, emerging targets, and novel therapeutic strategies

Clinical Science ◽

10.1042/cs20191213 ◽

2020 ◽

Vol 134 (17) ◽

pp. 2243-2262

Author(s):

Danlin Liu ◽

Gavin Richardson ◽

Fehmi M. Benli ◽

Catherine Park ◽

João V. de Souza ◽

...

Keyword(s):

Cardiovascular Diseases ◽

Cardiovascular System ◽

Nlrp3 Inflammasome ◽

Molecular Mechanisms ◽

Molecular Targets ◽

Therapeutic Interventions ◽

Low Grade ◽

Cardiovascular Research ◽

Inflammatory Processes ◽

Ach Receptors

Abstract In the elderly population, pathological inflammation has been associated with ageing-associated diseases. The term ‘inflammageing’, which was used for the first time by Franceschi and co-workers in 2000, is associated with the chronic, low-grade, subclinical inflammatory processes coupled to biological ageing. The source of these inflammatory processes is debated. The senescence-associated secretory phenotype (SASP) has been proposed as the main origin of inflammageing. The SASP is characterised by the release of inflammatory cytokines, elevated activation of the NLRP3 inflammasome, altered regulation of acetylcholine (ACh) nicotinic receptors, and abnormal NAD+ metabolism. Therefore, SASP may be ‘druggable’ by small molecule therapeutics targeting those emerging molecular targets. It has been shown that inflammageing is a hallmark of various cardiovascular diseases, including atherosclerosis, hypertension, and adverse cardiac remodelling. Therefore, the pathomechanism involving SASP activation via the NLRP3 inflammasome; modulation of NLRP3 via α7 nicotinic ACh receptors; and modulation by senolytics targeting other proteins have gained a lot of interest within cardiovascular research and drug development communities. In this review, which offers a unique view from both clinical and preclinical target-based drug discovery perspectives, we have focused on cardiovascular inflammageing and its molecular mechanisms. We have outlined the mechanistic links between inflammageing, SASP, interleukin (IL)-1β, NLRP3 inflammasome, nicotinic ACh receptors, and molecular targets of senolytic drugs in the context of cardiovascular diseases. We have addressed the ‘druggability’ of NLRP3 and nicotinic α7 receptors by small molecules, as these proteins represent novel and exciting targets for therapeutic interventions targeting inflammageing in the cardiovascular system and beyond.

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Periodontal Pathogens and Neuropsychiatric Health

Current Topics in Medicinal Chemistry ◽

10.2174/1568026620666200110161105 ◽

2020 ◽

Vol 20 (15) ◽

pp. 1353-1397 ◽

Cited By ~ 3

Author(s):

Abhishek Wadhawan ◽

Mark A. Reynolds ◽

Hina Makkar ◽

Alison J. Scott ◽

Eileen Potocki ◽

...

Keyword(s):

Molecular Mechanisms ◽

Metabolic Diseases ◽

Low Grade ◽

Periodontal Pathogens ◽

Synergistic Interactions ◽

Brain Vasculature ◽

Micro Rnas ◽

Clinical Conditions ◽

Low Grade Inflammation ◽

Neuropsychiatric Illness

Increasing evidence incriminates low-grade inflammation in cardiovascular, metabolic diseases, and neuropsychiatric clinical conditions, all important causes of morbidity and mortality. One of the upstream and modifiable precipitants and perpetrators of inflammation is chronic periodontitis, a polymicrobial infection with Porphyromonas gingivalis (P. gingivalis) playing a central role in the disease pathogenesis. We review the association between P. gingivalis and cardiovascular, metabolic, and neuropsychiatric illness, and the molecular mechanisms potentially implicated in immune upregulation as well as downregulation induced by the pathogen. In addition to inflammation, translocation of the pathogens to the coronary and peripheral arteries, including brain vasculature, and gut and liver vasculature has important pathophysiological consequences. Distant effects via translocation rely on virulence factors of P. gingivalis such as gingipains, on its synergistic interactions with other pathogens, and on its capability to manipulate the immune system via several mechanisms, including its capacity to induce production of immune-downregulating micro-RNAs. Possible targets for intervention and drug development to manage distal consequences of infection with P. gingivalis are also reviewed.

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The role of heredity in cancer.

Journal of Clinical Oncology ◽

10.1200/jco.1989.7.4.527 ◽

1989 ◽

Vol 7 (4) ◽

pp. 527-540 ◽

Cited By ~ 19

Author(s):

E G Levine ◽

R A King ◽

C D Bloomfield

Keyword(s):

Molecular Mechanisms ◽

Familial Cancer ◽

Tumor Development ◽

Future Research ◽

Minor Role ◽

Research Activity ◽

Environmental Interactions ◽

Future Research Directions ◽

A Minor

Heredity is generally felt to play a minor role in the development of cancer. This review critically examines this assumption. Topics discussed include evidence for heritable predisposition in animals and humans; the potential importance of genetic-environmental interactions; approaches that are being used to successfully locate genes responsible for heritable predisposition; comparability of genetic findings among heritable and corresponding sporadic malignancies; and future research directions. Breast, colon, and lung cancer are used to exemplify clinical and research activity in familial cancer; clinical phenotypes, segregation and linkage analyses, models for environmental interactions with inherited traits, and molecular mechanisms of tumor development are discussed. We conclude that the contribution of heredity to the cancer burden is greater than generally accepted, and that study of heritable predisposition will continue to reveal carcinogenic mechanisms important to the development of all cancers.

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Association of +505A>G Polymorphism at TAFI Gene with Recurrent Miscarriage in Iranian Women

World Journal of Peri & Neonatology ◽

10.18502/wjpn.v3i2.6156 ◽

2021 ◽

Author(s):

Razieh Alivand ◽

Fatemeh Abdi ◽

Mahmood Dehghani-Ashkezari ◽

Hossein Neamatzadeh ◽

Sedigheh Ekraminasab

Keyword(s):

Recurrent Miscarriage ◽

Iranian Women ◽

Specific Pcr ◽

Study Results ◽

Significant Difference ◽

Fibrinolysis Inhibitor ◽

History Of ◽

Allele Specific ◽

Allele Specific Pcr ◽

Control Study

Background: Recurrent miscarriage (RM) is one of the major problems of public health globally. The thrombin-activatable fibrinolysis inhibitor (TAFI) gene is a plasma zymogen that regulates both fibrinolysis and inflammation. Genetic variants within TAFI gene are presumed to be associated with development of RM. This case-control study aimed to investigate the association of TAFI +505A>G polymorphism with RM in Iranian women referred to Meybod Genetic Center. Methods: Fifty women with RM (at least 2 miscarriages) and 50 healthy women with no history of miscarriage or other fertility complications were participated in this study. The TAFI +505A>G polymorphism was genotyped by allele specific PCR (AS-PCR) assay. Results: The mean age of cases with RM and controls was 27.25 ± 4.31 and 28.42 ± 3.22 years, respectively. The frequency of GG genotype and G allele was 0.00% in patients and controls. There was no significant difference between RM cases and controls in terms of +505A>G genotypes and alleles. Conclusion: This study results indicated that there was no significant relationship between the TAFI +505A>G polymorphism and RM risk in Iranian women. However, further rigorous, studies with a larger sample size and different ethnicity are necessary to confirm our findings.

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EPCO-17. METHYLATION ANALYSIS OF MATCHED PRIMARY AND RECURRENT IDHmt ASTROCYTOMA; AN UPDATE FROM THE GLIOMA LONGITUDINAL ANALYSIS NL (GLASS-NL) CONSORTIUM

Neuro-Oncology ◽

10.1093/neuonc/noab196.016 ◽

2021 ◽

Vol 23 (Supplement_6) ◽

pp. vi5-vi5

Author(s):

Wies Vallentgoed ◽

Anneke Niers ◽

Karin van Garderen ◽

Martin van den Bent ◽

Kaspar Draaisma ◽

...

Keyword(s):

Dna Methylation ◽

Surgical Resection ◽

Molecular Mechanisms ◽

Relative Proportion ◽

Low Grade ◽

High Grade ◽

Primary Tumors ◽

Genome Wide ◽

Dna Methylation Profiling ◽

Methylation Profiling

Abstract The GLASS-NL consortium, was initiated to gain insight into the molecular mechanisms underlying glioma evolution and to identify markers of progression in IDH-mutant astrocytomas. Here, we present the first results of genome-wide DNA-methylation profiling of GLASS-NL samples. 110 adult patients were identified with an IDH-mutant astrocytoma at first diagnosis. All patients underwent a surgical resection of the tumor at least twice, separated by at least 6 months (median 40.9 months (IQR: 24.0, 64.7). In 37% and 18% of the cases, patients were treated with radiotherapy or chemotherapy respectively, before surgical resection of the recurrent tumor. DNA-methylation profiling was done on 235 samples from 103 patients (102 1st, 101 2nd, 29 3rd, and 3 4th resection). Copy number variations were also extracted from these data. Methylation classes were determined according to Capper et al. Overall survival (OS) was measured from date of first surgery. Of all primary tumors, the methylation-classifier assigned 85 (87%) to the low grade subclass and 10 (10%) to the high grade subclass. The relative proportion of high grade tumors increased ~three-fold at tumor recurrence (32/101, 32%) and even further in the second recurrence (15/29, 52%). Methylation classes were prognostic, both in primary and recurrent tumors. The overall DNA-methylation levels of recurrent samples was lower than that of primary samples. This difference is explained by the increased number of high grade samples at recurrence, since near identical DNA-methylation levels were observed in samples that remained low grade. In an unsupervised analysis, DNA-methylation data derived from primary and first recurrence samples of individual patients mostly (79%) cluster together. Recurrent samples that do not cluster with their primary tumor, form a separate group with relatively low genome-wide DNA-methylation. Our data demonstrate that methylation profiling identifies a shift towards a higher grade at tumor progression coinciding with reduced genome-wide DNA-methylation levels.

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Design and Analysis of a High Power Density, Low Temperature Waste Heat Recovery System Using an Oil-Free Turboalternator

Volume 5: Energy Systems Analysis, Thermodynamics and Sustainability; NanoEngineering for Energy; Engineering to Address Climate Change, Parts A and B ◽

10.1115/imece2010-40609 ◽

2010 ◽

Author(s):

James F. Walton ◽

Andrew Hunsberger ◽

Hooshang Heshmat

Keyword(s):

Output Power ◽

Waste Heat ◽

Maximum Output Power ◽

Output Power Level ◽

Working Fluid ◽

Prototype System ◽

Low Grade ◽

Maximum Output ◽

Test Results ◽

Study Results

In this paper the authors will present the design and preliminary test results for a distributed electric generating system that uses renewable energy source for economical load-following and peak-shaving capability in an oil-free, high-speed micro-turboalternator system using compliant foil bearings and a permanent magnet alternator. Test results achieved with the prototype system operating to full speed and under power generating mode will be presented. A comparison between predicted and measured electrical output will also be presented up to a power generating level of 25 kWe at approximately 55,000 rpm. The excellent correlation between design and test provides the basis for scale up to larger power levels. Based upon the turboalternator test results a thermodynamic cycle analysis of a system using low grade waste heat water at approximately 100 C will be reviewed. The tradeoff study results for a series of environmentally friendly refrigerant working fluids will also be presented including sensitivity to vaporization and condensing temperatures. Based on the cycle and pinch point analyses predicted maximum output power was determined. Finally a preliminary turbine design for the selected R134a working fluid was completed. The results of this study show that a net output power level of greater than 40 kW is possible for approximately 240 l/m flow of water at 100C is possible.

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