International Agency for Research on Cancer IARC

Cosne-Cours-sur-Loire, France

International Agency for Research on Cancer IARC

Cosne-Cours-sur-Loire, France
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Gospodinov A.,Bulgarian Academy of Science | Herceg Z.,International Agency for Research on Cancer IARC
Mutation Research - Reviews in Mutation Research | Year: 2013

To counteract the adverse effects of various DNA lesions, cells have evolved an array of diverse repair pathways to restore DNA structure and to coordinate repair with cell cycle regulation. Chromatin changes are an integral part of the DNA damage response, particularly with regard to the types of repair that involve assembly of large multiprotein complexes such as those involved in double strand break (DSB) repair and nucleotide excision repair (NER). A number of phosphorylation, acetylation, methylation, ubiquitylation and chromatin remodeling events modulate chromatin structure at the lesion site. These changes demarcate chromatin neighboring the lesion, afford accessibility and binding surfaces to repair factors and provide on-the-spot means to coordinate repair and damage signaling. Thus, the hierarchical assembly of repair factors at a double strand break is mostly due to their regulated interactions with posttranslational modifications of histones. A large number of chromatin remodelers are required at different stages of DSB repair and NER. Remodelers physically interact with proteins involved in repair processes, suggesting that chromatin remodeling is a requisite for repair factors to access the damaged site. Together, recent findings define the roles of histone post-translational modifications and chromatin remodeling in the DNA damage response and underscore possible differences in the requirements for these events in relation to the chromatin context. © 2012 Elsevier B.V.


Nogueira da Costa A.,International Agency for Research on Cancer IARC | Herceg Z.,International Agency for Research on Cancer IARC
Molecular Oncology | Year: 2012

The genetic and epigenetic material originating from tumour that can be found in body fluids of individuals with cancer harbours tumour-specific alterations and represents an attractive target for biomarker discovery. Epigenetic changes (DNA methylation, histone modifications and non-coding RNAs) are present ubiquitously in virtually all types of human malignancies and may appear in early cancer development, and thus they provide particularly attractive markers with broad applications in diagnostics. In addition, because changes in the epigenome may constitute a signature of specific exposure to certain risk factors, they have the potential to serve as highly specific biomarkers for risk assessment. While reliable detection of cancer-specific epigenetic changes has proven to be technically challenging, a substantial progress has been made in developing the methodologies that allow an efficient and sensitive detection of epigenomic changes using the material originating from body fluids. In this review we discuss the application of epigenomics as a tool for biomarker research, with the focus on the analysis of DNA methylation in biofluids. © 2012 Federation of European Biochemical Societies.


Romieu I.,International Agency for Research on Cancer IARC
Salud Publica de Mexico | Year: 2011

Both diet and nutrition have been studied in relationship with breast cancer risk, as the great variation among different countries in breast cancer incidence could possibly be explained through the inflammatory and immune response, as well as antioxidant intake, among others. To date, no clear association with diet beyond overweight and weight gain has been found, except for alcohol consumption. Nonetheless, the small number of studies done in middle to low income countries where variability of food intake is wider, is beginning to show interesting results.


Sincic N.,University of Zagreb | Herceg Z.,International Agency for Research on Cancer IARC
Current Opinion in Oncology | Year: 2011

Purpose of review: To discuss recent advances in the field of DNA methylation and their impact on our understanding of the role of this epigenetic mechanism in cancer development, as well as their implications for biomarker discovery and therapy. Recent findings: Epigenetics is a new frontier in cancer research with tremendous impact on our thinking and understanding of biological phenomena and complex diseases, notably cancer. Over the past decade there has been remarkable progress in our knowledge of the importance of epigenetic events in the control of both normal cellular processes and abnormal events associated with tumor development and progression. DNA methylation is a major epigenetic mechanism that is most intensively studied in the context of gene regulation and unscheduled silencing in cancer cells. Although hypermethylation of gene promoters is in turn associated with gene inactivation, the precise consequences of genome-wide hypomethylation are still debated. Recent studies have shed new light on the mechanisms underlying both promoter-specific hypermethylation and global hypomethylation in cancer cells and identified potential targets for biomarker discovery and therapeutic intervention. Summary: Recent conceptual advances in the field of DNA methylation and the advent and rapid development of new technologies in epigenomics have started to unravel the mechanisms underlying aberrant DNA methylation in cancer cells and identify novel targets for diagnosis, risk assessment and therapy. © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Herceg Z.,International Agency for Research on Cancer IARC | Vaissiere T.,International Agency for Research on Cancer IARC
Epigenetics | Year: 2011

Although epidemiological studies support the role of the environment in a wide range of human cancers, the precise mechanisms by which environmental exposures promote cancer development and progression remain poorly understood. Environmental factors have been proposed to promote the development of malignancies by eliciting epigenetic changes; however, it is only with recent advances in epigenetics and epigenomics that target genes and the mechanisms underlying environmental influences are beginning to be elucidated. Because epigenetic mechanisms may function as an interface between environmental factors and the genome, deregulation of the epigenome by environmental stressors is likely to disrupt different cellular processes and contribute to cancer risk. In addition, the early appearance and ubiquity of epigenetic changes in virtually all steps of tumor development and progression in most, if not all, human neoplasms, make them attractive targets for biomarker discovery and targeted prevention. At the cellular level, aberrant epigenetic changes associated with environmental exposures may deregulate key cellular processes (including transcriptional control, DNA repair, cell cycle control and carcinogen detoxification), which can be further modulated by environmental stressors, thus defining not only the phenotype of the disease but also potential biomarkers. This review summarizes recent progress in our understanding of the epigenetic mechanisms through which environmental factors may promote tumor development, with a particular focus on human lung cancer. © 2011 Landes Bioscience.


Schuz J.,International Agency for Research on Cancer IARC
Progress in Biophysics and Molecular Biology | Year: 2011

There is an ongoing scientific controversy whether the observed association between exposure to residential extremely low-frequency magnetic fields (ELF-MF) and the risk of childhood leukaemia observed in epidemiological studies is causal or due to methodological shortcomings of those studies. Recent pooled analysis confirm results from previous studies, namely an approximately two-fold risk increase at ELF-MF exposures ≥0.4 μT, and demonstrate consistency of studies across countries, with different design, different methods of exposure assessment, and different systems of power transmission and distribution. On the other hand, recent pooled analyses for childhood brain tumour show little evidence for an association with ELF-MF, also at exposures ≥0.4 μT. Overall, the assessment that ELF-MF are a possible carcinogen and may cause childhood leukaemia remains valid. Ongoing research activities, mainly experimental and few new epidemiological studies, hopefully provide additional insight to bring clarity to a research area that has remained inconclusive. © 2011 Elsevier Ltd.


Brennan P.,International Agency for Research on Cancer IARC | Hainaut P.,International Agency for Research on Cancer IARC | Boffetta P.,International Agency for Research on Cancer IARC | Boffetta P.,Mount Sinai School of Medicine
The Lancet Oncology | Year: 2011

Lung cancer is the most common form of cancer death worldwide. Although reduction of tobacco consumption remains the most appropriate strategy to reduce lung-cancer burden, identification of genes involved in the cause of disease could contribute to further understanding of the underlying mechanisms, and eventually lead to additional prevention strategies and targeted treatments. Common gene variants involved in lung cancer have been recently identified through large, collaborative, genome-wide association studies. These studies identified three separate loci that are associated with lung cancer (5p15, 6p21, and 15q25) and include genes that regulate acetylcholine nicotinic receptors and telomerase production. However, much about genetic risk remains to be discovered, and rarer gene variants, such as those of the CHEK2 gene, likely account for most of the remaining risk. There is also a need for studies that investigate how genetic susceptibility is associated with clinical outcome measures, including treatment response and tumour relapse. © 2011 Elsevier Ltd.


Hernandez-Vargas H.,International Agency for Research on Cancer IARC
BMC biotechnology | Year: 2014

BACKGROUND: Neonatal dried blood spots (DBS) represent an inexpensive method for long-term biobanking worldwide and are considered gold mines for research for several human diseases, including those of metabolic, infectious, genetic and epigenetic origin. However, the utility of DBS is restricted by the limited amount and quality of extractable biomolecules (including DNA), especially for genome wide profiling. Degradation of DNA in DBS often occurs during storage and extraction. Moreover, amplifying small quantities of DNA often leads to a bias in subsequent data, particularly in methylome profiles. Thus it is important to develop methodologies that maximize both the yield and quality of DNA from DBS for downstream analyses.RESULTS: Using combinations of in-house-derived and modified commercial extraction kits, we developed a robust and efficient protocol, compatible with methylome studies, many of which require stringent bisulfite conversion steps. Several parameters were tested in a step-wise manner, including blood extraction, cell lysis, protein digestion, and DNA precipitation, purification and elution. DNA quality was assessed based on spectrophotometric measurements, DNA detectability by PCR, and DNA integrity by gel electrophoresis and bioanalyzer analyses. Genome scale Infinium HumanMethylation450 and locus-specific pyrosequencing data generated using the refined DBS extraction protocol were of high quality, reproducible and consistent.CONCLUSIONS: This study may prove useful to meet the increased demand for research on prenatal, particularly epigenetic, origins of human diseases and for newborn screening programs, all of which are often based on DNA extracted from DBS.


Krutovskikh V.A.,International Agency for Research on Cancer IARC | Herceg Z.,International Agency for Research on Cancer IARC
BioEssays | Year: 2010

Small non-coding RNAs (microRNAs or miRs) represent one of the most fertile areas of cancer research and recent advances in the field have prompted us to reconsider the traditional concept of cancer. Some miRs exert negative control over the expression of numerous oncoproteins in normal cells and consequently their deregulation is believed to be an important mechanism underlying cancer development and progression. Owing to their distinct patterns of expression associated with cancer type, remarkable stability and presence in blood and other body fluids, miRs are considered to be highly promising cancer biomarkers. The identification of "miR signatures" associating cancer cell phenotypes with disease outcome and specific risk factor exposures will undoubtedly open new avenues for early diagnosis and therapy of cancer, as well as for the development of novel strategies for cancer prevention. © 2010 Wiley Periodicals, Inc.


Martin M.,International Agency for Research on Cancer IARC | Herceg Z.,International Agency for Research on Cancer IARC
Genome Medicine | Year: 2012

Inflammation represents the body's natural response to tissue damage; however, chronic inflammation may activate cell proliferation and induce deregulation of cell death in affected tissues. Chronic inflammation is an important factor in the development of hepatocellular carcinoma (HCC), although the precise underlying mechanism remains unknown. Epigenetic events, which are considered key mechanisms in the regulation of gene activity states, are also commonly deregulated in HCC. Here, we review the evidence that chronic inflammation might deregulate epigenetic processes, thus promoting oncogenic transformation, and we propose a working hypothesis that epigenetic deregulation is an underlying mechanism by which inflammation might promote HCC development. In this scenario, different components of the inflammatory response might directly and indirectly induce changes in epigenetic machineries ('epigenetic switch'), including those involved in setting and propagating normal patterns of DNA methylation, histone modifications and non-coding RNAs in hepatocytes. We discuss the possibility that self-reinforcing cross-talk between inflammation and epigenetic mechanisms might amplify inflammatory signals and maintain a chronic state of inflammation culminating in cancer development. The potential role of inflammation-epigenome interactions in the emergence and maintenance of cancer stem cells is also discussed. © 2012 BioMed Central Ltd.

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