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1.
Hippokratia ; 27(1): 7-11, 2023.
Article in English | MEDLINE | ID: mdl-38533226

ABSTRACT

Aim: Carcinogenesis of colorectal cancer is a process involving genetic mutations and epigenetic alterations in its multiple phases. The most considerable epigenetic alteration occurring in colorectal cancer (CRC) tumorigenesis is the methylation-mediated silencing of tumor suppressor genes. The present study aimed to detect the methylation status of SOX17 and WNT5a promoters in cell-free DNA circulating in plasma of metastatic CRC patients and to investigate potential prognostic correlation. Methods: A methylation-specific real-time polymerase chain reaction was utilized to investigate the methylation status of genes (SOX17 and WNT5a) promoter in the blood of 85 metastatic CRC patients. Results: We found the SOX17 promoter methylated in 54/85 (63.5 %) while WNT5a was methylated in 39/85 (45.8 %) samples of the advanced CRC. All control samples were negative for SOX17 and WNT5a promoter methylation. Patients with metastatic CRC and methylated SOX17 and WNT5a promoter status had a significantly poorer outcome than patients with non-methylated ones. Conclusions: Plasma SOX17 and WNT5a promoter methylation are frequent epigenetic events in advanced CRC. The reported correlations between the methylation status of genes (SOX17 and Wnt5a) promoter and poorer survival in patients with advanced CRC disease agree with the proposed role of SOX17 as a tumor suppressor gene. A more considerable CRC patient cohort is required to research these findings' potential further and investigate whether SOX17 in plasma could serve as a useful prognostic biomarker in metastatic CRC. HIPPOKRATIA 2023, 27 (1):7-11.

2.
Mutat Res ; 778: 46-51, 2015 Aug.
Article in English | MEDLINE | ID: mdl-26073472

ABSTRACT

Gastric carcinogenesis is a multistep process including not only genetic mutations but also epigenetic alterations. The best known and more frequent epigenetic alteration is DNA methylation affecting tumor suppressor genes that may be involved in various carcinogenetic pathways. The aim of the present study was to investigate the methylation status of APC promoter 1A and RASSF1A promoter in cell free DNA of operable gastric cancer patients. Using methylation specific PCR, we examined the methylation status of APC promoter 1A and RASSF1A promoter in 73 blood samples obtained from patients with gastric cancer. APC and RASSF1A promoters were found to be methylated in 61 (83.6%) and 50 (68.5%) of the 73 gastric cancer samples examined, but in none of the healthy control samples (p < 0.001). A significant association between methylated RASSF1A promoter status and lymph node positivity was observed (p = 0.005). Additionally, a significant correlation between a methylated APC promoter and elevated CEA (p = 0.033) as well as CA-19.9 (p = 0.032) levels, was noticed. The Kaplan-Meier estimates of survival, significantly favored patients with a non-methylated APC promoter status (p = 0.008). No other significant correlations between APC and RASSF1A methylation status and different tumor variables examined was observed. Serum RASSF1A and APC promoter hypermethylation is a frequent epigenetic event in patients with early operable gastric cancer. The observed correlations between APC promoter methylation status and survival as well as between a hypermethylated RASSF1A promoter and nodal positivity may be indicative of a prognostic role for those genes in early operable gastric cancer. Additional studies, in a larger cohort of patients are required to further explore whether these findings could serve as potential molecular biomarkers of survival and/or response to specific treatments.


Subject(s)
Carcinoma/genetics , DNA Methylation , DNA, Neoplasm/genetics , Genes, APC , Promoter Regions, Genetic , Stomach Neoplasms/genetics , Tumor Suppressor Proteins/genetics , Adult , Aged , Aged, 80 and over , Biomarkers, Tumor/blood , CA-19-9 Antigen/blood , Carcinoembryonic Antigen/analysis , Carcinoma/blood , Carcinoma/mortality , Carcinoma/secondary , Carcinoma/surgery , DNA, Neoplasm/blood , Female , Humans , Kaplan-Meier Estimate , Lymphatic Metastasis , Male , Middle Aged , Proportional Hazards Models , Stomach Neoplasms/blood , Stomach Neoplasms/mortality , Stomach Neoplasms/surgery
3.
Br J Cancer ; 110(8): 2054-62, 2014 Apr 15.
Article in English | MEDLINE | ID: mdl-24642624

ABSTRACT

BACKGROUND: Breast-cancer metastasis suppressor 1 (BRMS1) gene encodes for a predominantly nuclear protein that differentially regulates the expression of multiple genes, leading to suppression of metastasis without blocking orthotropic tumour growth. The aim of the present study was to evaluate for the first time the prognostic significance of BRMS1 promoter methylation in cell-free DNA (cfDNA) circulating in plasma of non-small cell lung cancer (NSCLC) patients. Towards this goal, we examined the methylation status of BRMS1 promoter in NSCLC tissues, matched adjacent non-cancerous tissues and corresponding cfDNA as well as in an independent cohort of patients with advanced NSCLC and healthy individuals. METHODS: Methylation of BRMS1 promoter was examined in 57 NSCLC tumours and adjacent non-cancerous tissues, in cfDNA isolated from 48 corresponding plasma samples, in cfDNA isolated from plasma of 74 patients with advanced NSCLC and 24 healthy individuals. RESULTS: The BRMS1 promoter was highly methylated both in operable NSCLC primary tissues (59.6%) and in corresponding cfDNA (47.9%) but not in cfDNA from healthy individuals (0%), while it was also highly methylated in cfDNA from advanced NSCLC patients (63.5%). In operable NSCLC, Kaplan-Meier estimates were significantly different in favour of patients with non-methylated BRMS1 promoter in cfDNA, concerning both disease-free interval (DFI) (P=0.048) and overall survival (OS) (P=0.007). In advanced NSCLC, OS was significantly different in favour of patients with non-methylated BRMS1 promoter in their cfDNA (P=0.003). Multivariate analysis confirmed that BRMS1 promoter methylation has a statistical significant influence both on operable NSCLC patients' DFI time and OS and on advanced NSCLC patients' PFS and OS. CONCLUSIONS: Methylation of BRMS1 promoter in cfDNA isolated from plasma of NSCLC patients provides important prognostic information and merits to be further evaluated as a circulating tumour biomarker.


Subject(s)
Carcinoma, Non-Small-Cell Lung/genetics , DNA Methylation/genetics , Neoplasm Proteins/blood , Adult , Aged , Biomarkers, Tumor/blood , Carcinoma, Non-Small-Cell Lung/blood , Carcinoma, Non-Small-Cell Lung/pathology , CpG Islands , DNA, Neoplasm/blood , DNA, Neoplasm/genetics , DNA, Neoplasm/isolation & purification , Disease-Free Survival , Female , Gene Expression Regulation, Neoplastic , Humans , Kaplan-Meier Estimate , Male , Middle Aged , Neoplasm Proteins/genetics , Neoplasm Proteins/isolation & purification , Neoplasm Staging , Neoplastic Cells, Circulating , Promoter Regions, Genetic , Repressor Proteins
4.
Neuropathol Appl Neurobiol ; 33(2): 212-25, 2007 Apr.
Article in English | MEDLINE | ID: mdl-17359362

ABSTRACT

Dysregulation of copper homeostasis has been associated with neurodegenerative diseases including Alzheimer's disease, amyotrophic lateral sclerosis (ALS) and prion diseases. The investigation of the role of abnormal copper level in the development of neuropathological damage is essential for the understanding of pathogenetic mechanisms of these neurodegenerative disorders. Using a mouse model of perinatally induced copper deficiency, the present study analysed the response of neuronal and glial cells to copper deficiency from infancy to young adult age. In mice born and maintained after weaning on copper-deficient diet, copper measurements indicated that at 6-8 weeks the copper levels in the brain were decreased by about 80% with respect to controls. In the brain of copper-deficient mice, microglial and astrocytic activation was observed, mostly in the cerebral cortex and thalamus. In addition, small vacuolated globoid cells confined to the subgranular zone of the dentate gyrus were found in the third postnatal week, and larger vacuolar profiles, identified as neuronal vacuoles, were observed in layer V of the cortex after the fourth week. The spatial distribution and temporal onset of vacuolation appeared to be unrelated to those of activated microglia and astrocytes. Nitrotyrosine-positivity was found to reflect the distribution of vacuoles in the cortex. The specific histopathological features here reported, as well as the severity of neurological deficits observed in this murine model of copper deficiency, strongly suggest that some hallmarks of neurodegenerative disorders could be mediated by multifactorial pathogenetic mechanisms that include copper dysregulation.


Subject(s)
Astrocytes/pathology , Copper/deficiency , Neurodegenerative Diseases/metabolism , Neurodegenerative Diseases/pathology , Neurons/pathology , Animal Feed , Animals , Astrocytes/metabolism , Behavior, Animal , Cerebral Cortex/metabolism , Cerebral Cortex/pathology , Copper/pharmacology , Dentate Gyrus/metabolism , Dentate Gyrus/pathology , Female , Male , Mice , Mice, Inbred Strains , Microglia/metabolism , Microglia/pathology , Neurodegenerative Diseases/etiology , Neurons/metabolism , Pregnancy , Thalamus/metabolism , Thalamus/pathology , Vacuoles/metabolism , Vacuoles/pathology
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