Wanderer, an interactive viewer to explore DNA methylation and gene expression data in human cancer

BACKGROUND: The Cancer Genome Atlas (TCGA) offers a multilayered view of genomics and epigenomics data of many human cancer types. However, the retrieval of expression and methylation data from TCGA is a cumbersome and time-consuming task.RESULTS:Wanderer is an intuitive Web tool allowing real time access and visualization of gene expression and DNA methylation profiles from TCGA. Given a gene query and selection of a TCGA dataset (e.g., colon adenocarcinomas), the Web resource provides the expression profile, at the single exon level, and the DNA methylation levels of HumanMethylation450 BeadChip loci inside or in the vicinity of the queried gene. Graphic and table outputs include individual and summary data as well as statistical tests, allowing the comparison of tumor and normal profiles and the exploration along the genomic locus and across tumor collections. CONCLUSIONS: Wanderer offers a simple interface to straightforward access to TCGA data, amenable to experimentalists and clinicians without bioinformatics expertise. Wanderer may be accessed at http://maplab.catwanderer

The epigenetic landscape of Alu repeats delineates the structural and functional genomic architecture of colon cancer cells

Cancer cells exhibit multiple epigenetic changes with prominent local DNA hypermethylation and widespread hypomethylation affecting large chromosomal domains. Epigenome studies often disregard the study of repeat elements owing to technical complexity and their undefined role in genome regulation. We have developed NSUMA (Next-generation Sequencing of UnMethylated Alu), a cost-effective approach allowing the unambiguous interrogation of DNA methylation in more than 130,000 individual Alu elements, the most abundant retrotransposon in the human genome. DNA methylation profiles of Alu repeats have been analyzed in colon cancers and normal tissues using NSUMA and whole-genome bisulfite sequencing. Normal cells show a low proportion of unmethylated Alu (1%-4%) that may increase up to 10-fold in cancer cells. In normal cells, unmethylated Alu elements tend to locate in the vicinity of functionally rich regions and display epigenetic features consistent with a direct impact on genome regulation. In cancer cells, Alu repeats are more resistant to hypomethylation than other retroelements. Genome segmentation based on high/low rates of Alu hypomethylation allows the identification of genomic compartments with differential genetic, epigenetic, and transcriptomic features. Alu hypomethylated regions show low transcriptional activity, late DNA replication, and its extent is associated with higher chromosomal instability. Our analysis demonstrates that Alu retroelements contribute to define the epigenetic landscape of normal and cancer cells and provides a unique resource on the epigenetic dynamics of a principal, but largely unexplored, component of the primate genome

Organochlorine exposure and colorectal cancer risk

Organochlorine compounds have been linked to increased risk of several cancers. Despite reductions in their use and fugitive release, they remain one of the most important groups of persistent pollutants to which humans are exposed, primarily through dietary intake. We designed a case-control study to assess the risk of colorectal cancer with exposure to these chemicals, and their potential interactions with genetic alterations in the tumors. A subsample of cases (n = 132) and hospital controls (n = 76) was selected from a larger case-control study in Barcelona, Catalonia, Spain. We measured concentrations in serum of several organochlorines by gas chromatography. We assessed point mutations in K-ras and p53 genes in tissue samples by polymerase chain reaction/single-strand conformation polymorphism and assessed expression of p53 protein by immunohistochemical methods. An elevated risk of colorectal cancer was associated with higher serum concentrations of mono-ortho polychlorinated biphenyl (PCB) congeners 28 and 118. The odds ratio for these mono-ortho PCBs for middle and higher tertile were, respectively, 1.82 [95% confidence interval (CI), 0.90-3.70] and 2.94 (95% CI, 1.39-6.20). alpha-Hexachlorocyclohexane, hexachlorobenzene, and pp'-DDE (4,4'-dichlorodiphenyltrichloroethene) showed nonsignificant increases in risk. Risk associated with mono-ortho PCBs was slightly higher for tumors with mutations in the p53 gene but was not modified by mutations in K-ras. Mono-ortho PCBs were further associated with transversion-type mutations in both genes. These results generate the hypothesis that exposure to mono-ortho PCBs contributes to human colorectal cancer development. The trend and magnitude of the association, as well as the observation of a molecular fingerprint in tumors, raise the possibility that this finding may be causal

Epigenetics override pro-inflammatory PTGS transcriptomic signature towards selective hyperactivation of PGE 2 in colorectal cancer

This is an Open Access article distributed under the terms of the Creative Commons Attribution License.-- et al.[Background]: Misregulation of the PTGS (prostaglandin endoperoxide synthase, also known as cyclooxygenase or COX) pathway may lead to the accumulation of pro-inflammatory signals, which constitutes a hallmark of cancer. To get insight into the role of this signaling pathway in colorectal cancer (CRC), we have characterized the transcriptional and epigenetic landscapes of the PTGS pathway genes in normal and cancer cells. [Results]: Data from four independent series of CRC patients (502 tumors including adenomas and carcinomas and 222 adjacent normal tissues) and two series of colon mucosae from 69 healthy donors have been included in the study. Gene expression was analyzed by real-time PCR and Affymetrix U219 arrays. DNA methylation was analyzed by bisulfite sequencing, dissociation curves, and HumanMethylation450K arrays. Most CRC patients show selective transcriptional deregulation of the enzymes involved in the synthesis of prostanoids and their receptors in both tumor and its adjacent mucosa. DNA methylation alterations exclusively affect the tumor tissue (both adenomas and carcinomas), redirecting the transcriptional deregulation to activation of prostaglandin E 2 (PGE 2 ) function and blockade of other biologically active prostaglandins. In particular, PTGIS, PTGER3, PTGFR, and AKR1B1 were hypermethylated in more than 40 % of all analyzed tumors. [Conclusions]: The transcriptional and epigenetic profiling of the PTGS pathway provides important clues on the biology of the tumor and its microenvironment. This analysis renders candidate markers with potential clinical applicability in risk assessment and early diagnosis and for the design of new therapeutic strategies.IC was funded by Fundação para a Ciência e a Tecnologia (SFRH/BD/28464/2006); JC was funded by a FPI fellowship. ADV was supported in part by a contract from the Ministerio de Economía y Competitividad (MINECO) (PTC2011-1091). This work was supported by the MINECO(SAF2011/23638, SAF2014/52492), the Catalan Institute of Oncology and the Instituto de Salud Carlos III (grant PI11-01439, RD12/0042/0019 and CIBERESP CB06/02/2005), the Generalitat de Catalunya (grant 2014SGR647), and the Asociación Española Contra el Cáncer (AECC).Peer Reviewe

Epigenetics override pro-inflammatory PTGS transcriptomic signature towards selective hyperactivation of PGE2 in colorectal cancer.

BACKGROUND: Misregulation of the PTGS (prostaglandin endoperoxide synthase, also known as cyclooxygenase or COX) pathway may lead to the accumulation of pro-inflammatory signals, which constitutes a hallmark of cancer. To get insight into the role of this signaling pathway in colorectal cancer (CRC), we have characterized the transcriptional and epigenetic landscapes of the PTGS pathway genes in normal and cancer cells. RESULTS: Data from four independent series of CRC patients (502 tumors including adenomas and carcinomas and 222 adjacent normal tissues) and two series of colon mucosae from 69 healthy donors have been included in the study. Gene expression was analyzed by real-time PCR and Affymetrix U219 arrays. DNA methylation was analyzed by bisulfite sequencing, dissociation curves, and HumanMethylation450K arrays. Most CRC patients show selective transcriptional deregulation of the enzymes involved in the synthesis of prostanoids and their receptors in both tumor and its adjacent mucosa. DNA methylation alterations exclusively affect the tumor tissue (both adenomas and carcinomas), redirecting the transcriptional deregulation to activation of prostaglandin E2 (PGE2) function and blockade of other biologically active prostaglandins. In particular, PTGIS, PTGER3, PTGFR, and AKR1B1 were hypermethylated in more than 40 % of all analyzed tumors. CONCLUSIONS: The transcriptional and epigenetic profiling of the PTGS pathway provides important clues on the biology of the tumor and its microenvironment. This analysis renders candidate markers with potential clinical applicability in risk assessment and early diagnosis and for the design of new therapeutic strategies

Factores psicosociales de riesgo y burnout en policías: un análisis de redes

Work stress has been identified as a critical factor affecting mental health in police officers. Psychosocial factors increase the impact of work stress on police officers and,in the long run,contribute to the onset of burnout symptoms. In this research asample of 323 was studied to study the relationship between psychosocial risk factors and the probability of suffering burnout symptoms. The participant’s answers to the MBI-GSandF-PSICO(version4.0) were analysed by using network analysis.There sults show that psychosocial risk factors are strongly associated in network models when higher level of cynicism and emotional exhaustion are observed. Additionally, higher levels of burnout in police officers were observed when lower autonomy,higher psychological demands, role ambiguities and alower perceived social support were present. Results are discussed considering its theoretical and applied relevance to design healthier work environments an defficient psychologicalinterventionsEl estrés laboral crónico ha sido identificado como uno de los riesgos laborales más importantes que afecta a la salud mental de los agentes de policía. Existen ciertos factores psicosociales que incrementan el estrés laboral en la policía y que, a largo plazo, desencadenan síntomas compatibles con el burnout. En este trabajo se ha utilizado una muestra integrada por 323 policías para valorar la relación que se establece entre los factores psicosociales de riesgo y la probabilidad de experimentar síntomas compatibles con el burnout. Las respuestas de los participantes al MBI-GS y al F-PSICO (versión 4.0) fueron examinadas utilizando análisis de redes. Los resultados muestran que existen redes de factores psicosociales de riesgo más cohesionadas cuando los niveles de cinismo y agotamiento emocional son más elevados. Además, se observa mayor nivel de burnout asociados con una baja autonomía, altas demandas psicológicas, conflictos en el desempeño de rol y un bajo apoyo social percibido. Los resultados son discutidos en términos de su implicación teórica y de su utilidad práctica frente al diseño de entornos de trabajo más saludables, así como frente a la intervención psicológica

Caveolin-1 is down-regulated in alveolar habdomyosarcomas and negatively regulates tumor growth

Rhabdomyosarcoma is the most common soft tissue sarcoma of childhood and adolescence. Despite advances in therapy, patients with histological variant of rhabdomyosarcoma known as alveolar rhabdomyosarcoma (ARMS) have a 5-year survival of less than 30%. Caveolin-1 (CAV1), encoding the structural component of cellular caveolae, is a suggested tumor suppressor gene involved in cell signaling. In the present study we report that compared to other forms of rhabdomyosarcoma (RMS) CAV1 expression is either undetectable or very low in ARMS cell lines and tumor samples. DNA methylation analysis of the promoter region and azacytidine-induced re-expression suggest the involvement of epigenetic mechanisms in the silencing of CAV1. Reintroduction of CAV1 in three of these cell lines impairs their clonogenic capacity and promotes features of muscular differentiation. In vitro, CAV1-expressing cells show high expression of Caveolin-3 (CAV3), a muscular differentiation marker. Blockade of MAPK signaling is also observed. In vivo, CAV1-expressing xenografts show growth delay, features of muscular differentiation and increased cell death. In summary, our results suggest that CAV1 could function as a potent tumor suppressor in ARMS tumors. Inhibition of CAV1 function therefore, could contribute to aberrant cell proliferation, leading to ARMS development

Quantification of unmethylated Alu (QUAlu): a tool to assess global hypomethylation in routine clinical samples

Hypomethylation of DNA is a hallmark of cancer and its analysis as tumor biomarker has been proposed, but its determination in clinical settings is hampered by lack of standardized methodologies. Here, we present QUAlu (Quantification of Unmethylated Alu), a new technique to estimate the Percentage of UnMethylated Alu (PUMA) as a surrogate for global hypomethylation. QUAlu consists in the measurement by qPCR of Alu repeats after digestion of genomic DNA with isoschizomers with differential sensitivity to DNA methylation. QUAlu performance has been evaluated for reproducibility, trueness and specificity, and validated by deep sequencing. As a proof of use, QUAlu has been applied to a broad variety of pathological examination specimens covering five cancer types. Major findings of the preliminary application of QUAlu to clinical samples include: (1) all normal tissues displayed similar PUMA; (2) tumors showed variable PUMA with the highest levels in lung and colon and the lowest in thyroid cancer; (3) stools from colon cancer patients presented higher PUMA than those from control individuals; (4) lung squamous cell carcinomas showed higher PUMA than lung adenocarcinomas, and an increasing hypomethylation trend associated with smoking habits. In conclusion, QUAlu is a simple and robust method to determine Alu hypomethylation in human biospecimens and may be easily implemented in research and clinical settings

Population structure in a highly pelagic seabird, the Cory's shearwater (Calonectris diomedea): an examination of genetics, morphology and ecology

Increasing evidence suggests oceanic traits may play a key role in the genetic structuring of marine organisms. Whereas genetic breaks in the open ocean are well known in fishes and marine invertebrates, the importance of marine habitat characteristics in seabirds remains less certain. We investigated the role of oceanic transitions versus population genetic processes in driving population differentiation in a highly vagile seabird, the Cory"s shearwater, combining molecular, morphological and ecological data from 27 breeding colonies distributed across the Mediterranean (Calonectris diomedea diomedea) and the Atlantic (C. d. borealis). Genetic and biometric analyses showed a clear differentiation between Atlantic and Mediterranean Cory"s shearwaters. Ringing-recovery data indicated high site fidelity of the species, but we found some cases of dispersal among neighbouring breeding sites (1000 km) within and between each basin. In agreement with this, comparison of phenotypic and genetic data revealed both current and historical dispersal events. Within each region, we did not detect any genetic substructure among archipelagos in the Atlantic, but we found a slight genetic differentiation between western and eastern breeding colonies in the Mediterranean. Accordingly, gene flow estimates suggested substantial dispersal among colonies within basins. Overall, genetic structure of the Cory"s shearwater matches main oceanographic breaks (Almería-Oran Oceanic Front and Siculo-Tunisian Strait), but spatial analyses suggest that patterns of genetic differentiation are better explained by geographic rather than oceanographic distances. In line with previous studies, genetic, phenotypic and ecological evidence supported the separation of Atlantic and Mediterranean forms, suggesting the 2 taxa should be regarded as different species