Beltrami C.M.,International Research Center Cipe Ac Camargo Cancer Center And National Institute Of Science And Technology In Oncogenomics Incito |
dos Reis M.B.,International Research Center Cipe Ac Camargo Cancer Center And National Institute Of Science And Technology In Oncogenomics Incito |
dos Reis M.B.,São Paulo State University |
Barros-Filho M.C.,International Research Center Cipe Ac Camargo Cancer Center And National Institute Of Science And Technology In Oncogenomics Incito |
And 10 more authors.
Clinical Epigenetics | Year: 2017
Background: Papillary thyroid carcinoma (PTC) is a common endocrine neoplasm with a recent increase in incidence in many countries. Although PTC has been explored by gene expression and DNA methylation studies, the regulatory mechanisms of the methylation on the gene expression was poorly clarified. In this study, DNA methylation profile (Illumina HumanMethylation 450K) of 41 PTC paired with non-neoplastic adjacent tissues (NT) was carried out to identify and contribute to the elucidation of the role of novel genic and intergenic regions beyond those described in the promoter and CpG islands (CGI). An integrative and cross-validation analysis were performed aiming to identify molecular drivers and pathways that are PTC-related. Results: The comparisons between PTC and NT revealed 4995 methylated probes (88% hypomethylated in PTC) and 1446 differentially expressed transcripts cross-validated by the The Cancer Genome Atlas data. The majority of these probes was found in non-promoters regions, distant from CGI and enriched by enhancers. The integrative analysis between gene expression and DNA methylation revealed 185 and 38 genes (mainly in the promoter and body regions, respectively) with negative and positive correlation, respectively. Genes showing negative correlation underlined FGF and retinoic acid signaling as critical canonical pathways disrupted by DNA methylation in PTC. BRAF mutation was detected in 68% (28 of 41) of the tumors, which presented a higher level of demethylation (95% hypomethylated probes) compared with BRAF wild-type tumors. A similar integrative analysis uncovered 40 of 254 differentially expressed genes, which are potentially regulated by DNA methylation in BRAFV600E-positive tumors. The methylation and expression pattern of six selected genes (ERBB3, FGF1, FGFR2, GABRB2, HMGA2, and RDH5) were confirmed as altered by pyrosequencing and RT-qPCR. Conclusions: DNA methylation loss in non-promoter, poor CGI and enhancer-enriched regions was a significant event in PTC, especially in tumors harboring BRAFV600E. In addition to the promoter region, gene body and 3’UTR methylation have also the potential to influence the gene expression levels (both, repressing and inducing). The integrative analysis revealed genes potentially regulated by DNA methylation pointing out potential drivers and biomarkers related to PTC development. © 2017, The Author(s).
Kettunen E.,Research and Service Center for Occupational Safety |
Hernandez-Vargas H.,Epigenetics Group |
Cros M.-P.,Epigenetics Group |
Durand G.,Genetic Cancer Susceptibility GroupSection of Genetics |
And 8 more authors.
International Journal of Cancer | Year: 2017
Previous studies have revealed a robust association between exposure to asbestos and human lung cancer. Accumulating evidence has highlighted the role of epigenome deregulation in the mechanism of carcinogen-induced malignancies. We examined the impact of asbestos on DNA methylation. Our genome-wide studies (using Illumina HumanMethylation450K BeadChip) of lung cancer tissue and paired normal lung from 28 asbestos-exposed or non-exposed patients, mostly smokers, revealed distinctive DNA methylation changes. We identified a number of differentially methylated regions (DMR) and differentially variable, differentially methylated CpGs (DVMC), with individual CpGs further validated by pyrosequencing in an independent series of 91 non-small cell lung cancer and paired normal lung. We discovered and validated BEND4, ZSCAN31 and GPR135 as significantly hypermethylated in lung cancer. DMRs in genes such as RARB (FDR 1.1 × 10-19, mean change in beta [Δ] -0.09), GPR135 (FDR 1.87 × 10-8, mean Δ -0.09) and TPO (FDR 8.58 × 10-5, mean Δ -0.11), and DVMCs in NPTN, NRG2, GLT25D2 and TRPC3 (all with p <0.05, t-test) were significantly associated with asbestos exposure status in exposed versus non-exposed lung tumors. Hypomethylation was characteristic to DVMCs in lung cancer tissue from asbestos-exposed subjects. When DVMCs related to asbestos or smoking were analyzed, 96% of the elements were unique to either of the exposures, consistent with the concept that the methylation changes in tumors may be specific for risk factors. In conclusion, we identified novel DNA methylation changes associated with lung tumors and asbestos exposure, suggesting that changes may be present in causal pathway from asbestos exposure to lung cancer. © 2017 UICC.
Heard E.,Epigenetics Group |
Tishkoff S.,University of Pennsylvania |
Todd J.A.,University of Cambridge |
Vidal M.,Dana-Farber Cancer Institute |
And 6 more authors.
Nature Reviews Genetics | Year: 2010
To celebrate the first 10 years of Nature Reviews Genetics, we asked eight leading researchers for their views on the key developments in genetics and genomics in the past decade and the prospects for the future. Their responses highlight the incredible changes that the field has seen, from the explosion of genomic data and the many possibilities it has opened up to the ability to reprogramme adult cells to pluripotency. The way ahead looks similarly exciting as we address questions such as how cells function as systems and how complex interactions among genetics, epigenetics and the environment combine to shape phenotypes. © 2010 Macmillan Publishers Limited. All rights reserved.
Devaney J.,Epigenetics Group |
Devaney J.,Garvan Institute of Medical Research |
Stirzaker C.,Epigenetics Group |
Stirzaker C.,Garvan Institute of Medical Research |
And 29 more authors.
Cancer Epidemiology Biomarkers and Prevention | Year: 2011
Background: Previously, we showed that gene suppression commonly occurs across chromosome 2ql4.2 in colorectal cancer, through a process of long-range epigenetic silencing (LRES), involving a combination of DNA methylation and repressive histone modifications. We now investigate whether LRES also occurs in prostate cancer across this 4-Mb region and whether differential DNA methylation of 2ql4.2 genes could provide a regional panel of prostate cancer biomarkers. Methods: We used highly sensitive DNA methylation headloop PCR assays that can detect 10 to 25 pg of methylated DNA with a specificity of at least 1:1,000, and chromatin immunoprecipitation assays to investigate regional epigenetic remodeling across 2q14.2 in prostate cancer, in a cohort of 195 primary prostate tumors and 90 matched normal controls. Results: Prostate cancer cells exhibit concordant deacetylation and methylation of histone H3 Lysine 9 (H3K9Ac and H3K9me2, respectively), and localized DNA hypermethylation of EN1, SCTR, and INHBB and corresponding loss of H3K27me3. EN1 and SCTR were frequently methylated (65% and 53%, respectively), whereas INHBB was less frequently methylated. Conclusions: Consistent with LRES in colorectal cancer, we found regional epigenetic remodeling across 2q14.2 in prostate cancer. Concordant methylation of EN1 and SCTR was able to differentiate cancer from normal (P < 0.0001) and improved the diagnostic specificity of GSTP1 methylation for prostate cancer detection by 26%. © 2011 American Association for Cancer Research.
Liechtenstein T.,University College London |
Liechtenstein T.,Immunomodulation Group |
Perez-Janices N.,University College London |
Perez-Janices N.,Epigenetics Group |
And 16 more authors.
Virus Research | Year: 2013
Our work over the past eight years has focused on the use of HIV-1 lentiviral vectors (lentivectors) for the genetic modification of dendritic cells (DCs) to control their functions in immune modulation. DCs are key professional antigen presenting cells which regulate the activity of most effector immune cells, including T, B and NK cells. Their genetic modification provides the means for the development of targeted therapies towards cancer and autoimmune disease. We have been modulating with lentivectors the activity of intracellular signalling pathways and co-stimulation during antigen presentation to T cells, to fine-tune the type and strength of the immune response. In the course of our research, we have found unexpected results such as the surprising immunosuppressive role of anti-viral signalling pathways, and the close link between negative co-stimulation in the immunological synapse and T cell receptor trafficking. Here we review our major findings and put them into context with other published work. © 2013 Elsevier B.V.
Escors D.,Immunomodulation group |
Escors D.,University College London |
Liechtenstein T.,University College London |
Perez-Janices N.,University College London |
And 3 more authors.
Immunology, Endocrine and Metabolic Agents in Medicinal Chemistry | Year: 2013
Since the first human gene therapy clinical trials were proven successful in 2000, human gene therapy has witnessed setbacks as well as encouraging progress. While these first clinical trials were performed with a γ-retrovirus vector to correct X-linked severe combined immunodeficiency (SCID-X1) in children, others since then have applied similar or alternative viral vector strategies. More recently, lentiviral vectors have been used for the correction of human (β-thalassaemia and adrenoleukodystrophy. They have also been successfully used in the treatment of leukaemia by modifying cytotoxic T cells directed to cancer cells. Here we describe the production of clinical grade retro- and lentiviral vectors for application in human therapy. © 2013 Bentham Science Publishers.
Grandin M.,University of Lyon |
Mathot P.,University of Lyon |
Devailly G.,University of Lyon |
Bidet Y.,Center Jean Perrin |
And 10 more authors.
EMBO Molecular Medicine | Year: 2016
In a number of human cancers, NTN1 upregulation inhibits apoptosis induced by its so-called dependence receptors DCC and UNC5H, thus promoting tumor progression. In other cancers however, the selective inhibition of this dependence receptor death pathway relies on the silencing of pro-apoptotic effector proteins. We show here that a substantial fraction of human breast tumors exhibits simultaneous DNA methylation-dependent loss of expression of NTN1 and of DAPK1, a serine threonine kinase known to transduce the netrin-1 dependence receptor pro-apoptotic pathway. The inhibition of DNA methylation by drugs such as decitabine restores the expression of both NTN1 and DAPK1 in netrin-1-low cancer cells. Furthermore, a combination of decitabine with NTN1 silencing strategies or with an anti-netrin-1 neutralizing antibody potentiates tumor cell death and efficiently blocks tumor growth in different animal models. Thus, combining DNA methylation inhibitors with netrin-1 neutralizing agents may be a valuable strategy for combating cancer. © 2016 The Authors. Published under the terms of the CC BY 4.0 license