BackgroundIn recent years, increasing amounts of genomic and clinical cancer data have become publically available through large-scale collaborative projects such as The Cancer Genome Atlas (TCGA). However, as long as these datasets are difficult to access and interpret, they are essentially useless for a major part of the research community and their scientific potential will not be fully realized. To address these issues we developed MEXPRESS, a straightforward and easy-to-use web tool for the integration and visualization of the expression, DNA methylation and clinical TCGA data on a single-gene level (http://mexpress.be).ResultsIn comparison to existing tools, MEXPRESS allows researchers to quickly visualize and interpret the different TCGA datasets and their relationships for a single gene, as demonstrated for GSTP1 in prostate adenocarcinoma. We also used MEXPRESS to reveal the differences in the DNA methylation status of the PAM50 marker gene MLPH between the breast cancer subtypes and how these differences were linked to the expression of MPLH.ConclusionsWe have created a user-friendly tool for the visualization and interpretation of TCGA data, offering clinical researchers a simple way to evaluate the TCGA data for their genes or candidate biomarkers of interest.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-015-1847-z) contains supplementary material, which is available to authorized users.

The recent growth in the number of publicly available cancer omics databases has been accompanied by the development of various tools that allow researchers to visually explore these data. In 2015, we built MEXPRESS, an online tool for the integration and visualization of gene expression, DNA methylation and clinical data from The Cancer Genome Atlas (TCGA), a large collection of publicly available multi-omics cancer data. MEXPRESS addresses the need for an easy-to-use, interactive application that allows researchers to identify dysregulated genes and their clinical relevance in cancer. Furthermore, while other tools typically do not support integrated visualization of expression and DNA methylation data in combination with the precise genomic location of the methylation, MEXPRESS is unique in how it depicts these diverse data types together. Motivated by the large number of users MEXPRESS has managed to attract over the past 3 years and the recent migration of all TCGA data to a new data portal, we developed a new version of MEXPRESS (https://mexpress.be). It contains the latest TCGA data, additional types of omics and clinical data and extra functionality, allowing users to explore mechanisms of gene dysregulation beyond expression and DNA methylation.

No abstract

Purpose: The importance of genetic and epigenetic alterations maybe in their aggregate role in altering core pathways in tumorigenesis.Experimental Design: Merging genome-wide genomic and epigenomic alterations, we identify key genes and pathways altered in colorectal cancers (CRC). DNA methylation analysis was tested for predicting survival in CRC patients using Cox proportional hazard model.Results: We identified 29 low frequency-mutated genes that are also inactivated by epigenetic mechanisms in CRC. Pathway analysis showed the extracellular matrix (ECM) remodeling pathway is silenced in CRC. Six ECM pathway genes were tested for their prognostic potential in large CRC cohorts (n ¼ 777). DNA methylation of IGFBP3 and EVL predicted for poor survival (IGFBP3: HR ¼ 2.58, 95% CI: 1.37-4.87, P ¼ 0.004; EVL: HR ¼ 2.48, 95% CI: 1.07-5.74, P ¼ 0.034) and simultaneous methylation of multiple genes predicted significantly worse survival (HR ¼ 8.61, 95% CI: 2.16-34.36, P < 0.001 for methylation of IGFBP3, EVL, CD109, and FLNC). DNA methylation of IGFBP3 and EVL was validated as a prognostic marker in an independent contemporary-matched cohort (IGFBP3 HR ¼ 2.06, 95% CI: 1.04-4.09, P ¼ 0.038; EVL HR ¼ 2.23, 95% CI: 1.00-5.0, P ¼ 0.05) and EVL DNA methylation remained significant in a secondary historical validation cohort (HR ¼ 1.41, 95% CI: 1.05-1.89, P ¼ 0.022). Moreover, DNA methylation of selected ECM genes helps to stratify the high-risk stage 2 colon cancers patients who would benefit from adjuvant chemotherapy (HR: 5.85, 95% CI: 2.03-16.83, P ¼ 0.001 for simultaneous methylation of IGFBP3, EVL, and CD109).Conclusions: CRC that have silenced genes in ECM pathway components show worse survival suggesting that our finding provides novel prognostic biomarkers for CRC and reflects the high importance of integrative analyses linking genetic and epigenetic abnormalities with pathway disruption in cancer. Clin Cancer Res; 17(6); 1535-45. Ó2011 AACR.

Purpose Genome-wide DNA methylation analyses have identified hundreds of candidate DNA-hypermethylated genes in cancer. Comprehensive functional analyses provide an understanding of the biologic significance of this vast amount of DNA methylation data that may allow the determination of key epigenetic events associated with tumorigenesis. Experimental Design To study mechanisms of cysteine dioxygenase type 1 (CDO1) inactivation and its functional significance in breast cancer in a comprehensive manner, we screened for DNA methylation and gene mutations in primary breast cancers and analyzed growth, survival, and reactive oxygen species (ROS) production in breast cancer cells with restored CDO1 function in the context of anthracycline treatment. Results DNA methylation-associated silencing of CDO1 in breast cancer is frequent (60%), cancer specific, and correlates with disease progression and outcome. CDO1 function can alternatively be silenced by repressive chromatin, and we describe protein-damaging missense mutations in 7% of tumors without DNA methylation. Restoration of CDO1 function in breast cancer cells increases levels of ROS and leads to reduced viability and growth, as well as sensitization to anthracycline treatment. Priming with 5-azacytidine of breast cancer cells with epigenetically silenced CDO1 resulted in restored expression and increased sensitivity to anthracyclines. Conclusion We report that silencing of CDO1 is a critical epigenetic event that contributes to the survival of oxidative-stressed breast cancer cells through increased detoxification of ROS and thus leads to the resistance to ROS-generating chemotherapeutics including anthracyclines. Our study shows the importance of CDO1 inactivation in breast cancer and its clinical potential as a biomarker and therapeutic target to overcome resistance to anthracyclines.

Innovative therapies for solid tumors are urgently needed. Recently, therapies that harness the host immune system to fight cancer cells have successfully treated a subset of patients with solid tumors. These responses have been strong and durable but observed in subsets of patients. Work from our group and others has shown that epigenetic therapy, specifically inhibiting the silencing DNA methylation mark, activates immune signaling in tumor cells and can sensitize to immune therapy in murine models. Here we show that colon and ovarian cancer cell lines exhibit lower expression of transcripts involved in antigen processing and presentation to immune cells compared to normal tissues. In addition, treatment with clinically relevant low doses of DNMT inhibitors (that remove DNA methylation) increases expression of both antigen processing and presentation and Cancer Testis Antigens in these cell lines. We confirm that treatment with DNMT inhibitors upregulates expression of the antigen processing and presentation molecules B2M, CALR, CD58, PSMB8, PSMB9 at the RNA and protein level in a wider range of colon and ovarian cancer cell lines and treatment time points than had been described previously. In addition, we show that DNMTi treatment upregulates many Cancer Testis Antigens common to both colon and ovarian cancer. This increase of both antigens and antigen presentation by epigenetic therapy may be one mechanism to sensitize patients to immune therapies.

(2012) Biomarkers for detection and prognosis of breast cancer identified by a functional hypermethylome screen, Epigenetics, 7:7, 701-709,

The diagnosis of sessile serrated adenomas (SSAs) is challenging, and there is a great deal of interobserver variability amongst pathologists in differentiating SSAs from hyperplastic polyps (HPPs). The aim of this study was (i) to assess the utility of epigenetic changes such as DNA methylation in differentiating SSAs from HPPs and (ii) to identify common methylation based molecular markers potentially useful for early detection of premalignant neoplastic lesions of gastrointestinal tract. A total of 97 primary patient adenoma samples were obtained from The Johns Hopkins Hospital pathology archive with IRB approval and HIPAA compliance. We analyzed the promoter associated CpG island methylation status of 17 genes using nested multiplex methylation specific PCR (MSP). Methylation of CDX2, hMLH1 and TLR2 was detected in SSAs and SSAs with dysplasia but not in HPPs. A subset of genes including EVL, GATAs (4 and 5), HIN-1, SFRPs (1, 2, 4 and 5), SOX17 and SYNE1 were methylated frequently in all premalignant gastrointestinal adenomas including tubular adenomas, villous adenomas, SSAs and SSAs with dysplasia but infrequently in non-premalignant polyps such as HPPs. Methylation of CDX2, hMLH1 and TLR2 may be of diagnostic utility in differentiating, histologically challenging cases of SSAs from HPPs. Genes such as EVL, GATAs, HIN-1, SFRPs, SOX17 and SYNE1, which are frequently methylated in all types of tested premalignant adenomas, may be useful as biomarkers in stool-based strategies for early detection of these adenomas and CRCs in future.