Meta-Analysis of DNA Methylation and Expression in Liver Cancer Patients

Hepatocellular carcinoma (HCC), the most common liver cancer, is the second leading cause of cancer-related death worldwide. HCC is often diagnosed at late stages, for which there are no effective chemotherapies. Biomarkers unique to HCC patients could be used to detect HCC early and improve treatment. In the present project, we have performed a meta-analysis to compare the gene-specific DNA methylation and gene expression patterns of HCC patients as reported by four independent studies. Our goal was to discover the strongest changes that distinguish HCC from normal tissue. The relationship between methylation and expression in HCC was examined and genes epigenetically regulated in HCC were identified. The top changes within genes, gene families and pathways could be of interest in further investigations of potential HCC biomarkers. A significant correlation between DNA hypomethylation and gene activation and between DNA hypermethylation and gene silencing was found. CpG islands, commonly found in promoter regions, are predominantly hypermethylated in HCC, while CpGs outside of CpG islands are predominantly hypomethylated in gene bodies. 149 genes were found to be significantly differentially methylated between tumors and normal adjacent tissue, and 169 genes were found to be significantly differentially expressed. Genes identified for further research are GNG7, WNT5B, RXRG, HOXB7, and SMARCB1. No overlap was found between differentially expressed and methylated genes. Nevertheless, common gene families and pathways were identified where more potential biomarkers could be found in future studies

The Role of Sulforaphane in Epigenetic Mechanisms, Including Interdependence between Histone Modification and DNA Methylation

Carcinogenesis as well as cancer progression result from genetic and epigenetic changes of the genome that leads to dysregulation of transcriptional activity of genes. Epigenetic mechanisms in cancer cells comprise (i) post-translation histone modification (i.e., deacetylation and methylation); (ii) DNA global hypomethylation; (iii) promoter hypermethylation of tumour suppressor genes and genes important for cell cycle regulation, cell differentiation and apoptosis; and (iv) posttranscriptional regulation of gene expression by noncoding microRNA. These epigenetic aberrations can be readily reversible and responsive to both synthetic agents and natural components of diet. A source of one of such diet components are cruciferous vegetables, which contain high levels of a number of glucosinolates and deliver, after enzymatic hydrolysis, sulforaphane and other bioactive isothiocyanates, that are involved in effective up-regulation of transcriptional activity of certain genes and also in restoration of active chromatin structure. Thus a consumption of cruciferous vegetables, treated as a source of isothiocyanates, seems to be potentially useful as an effective cancer preventive factor or as a source of nutrients improving efficacy of standard chemotherapies. In this review an attempt is made to elucidate the role of sulforaphane in regulation of gene promoter activity through a direct down-regulation of histone deacetylase activity and alteration of gene promoter methylation in indirect ways, but the sulforaphane influence on non-coding micro-RNA will not be a subject of this review

Comparative proteome analysis revealing an 11-protein signature for aggressive triple-negative breast cancer

Item does not contain fulltextBACKGROUND: Clinical outcome of patients with triple-negative breast cancer (TNBC) is highly variable. This study aims to identify and validate a prognostic protein signature for TNBC patients to reduce unnecessary adjuvant systemic therapy. METHODS: Frozen primary tumors were collected from 126 lymph node-negative and adjuvant therapy-naive TNBC patients. These samples were used for global proteome profiling in two series: an in-house training (n = 63) and a multicenter test (n = 63) set. Patients who remained free of distant metastasis for a minimum of 5 years after surgery were defined as having good prognosis. Cox regression analysis was performed to develop a prognostic signature, which was independently validated. All statistical tests were two-sided. RESULTS: An 11-protein signature was developed in the training set (median follow-up for good-prognosis patients = 117 months) and subsequently validated in the test set (median follow-up for good-prognosis patients = 108 months) showing 89.5% sensitivity (95% confidence interval [CI] = 69.2% to 98.1%), 70.5% specificity (95% CI = 61.7% to 74.2%), 56.7% positive predictive value (95% CI = 43.8% to 62.1%), and 93.9% negative predictive value (95% CI = 82.3% to 98.9%) for poor-prognosis patients. The predicted poor-prognosis patients had higher risk to develop distant metastasis than the predicted good-prognosis patients in univariate (hazard ratio [HR] = 13.15; 95% CI = 3.03 to 57.07; P = .001) and multivariable (HR = 12.45; 95% CI = 2.67 to 58.11; P = .001) analysis. Furthermore, the predicted poor-prognosis group had statistically significantly more breast cancer-specific mortality. Using our signature as guidance, more than 60% of patients would have been exempted from unnecessary adjuvant chemotherapy compared with conventional prognostic guidelines. CONCLUSIONS: We report the first validated proteomic signature to assess the natural course of clinical TNBC