OncoMethylome science SA

Liège, Belgium

OncoMethylome science SA

Liège, Belgium
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Eijsink J.J.H.,University of Groningen | Lendvai A.,University of Groningen | Deregowski V.,OncoMethylome Science S.A. | Klip H.G.,University of Groningen | And 8 more authors.
International Journal of Cancer | Year: 2012

Cervical neoplasia-specific biomarkers, e.g. DNA methylation markers, with high sensitivity and specificity are urgently needed to improve current population-based screening on (pre)malignant cervical neoplasia. We aimed to identify new cervical neoplasia-specific DNA methylation markers and to design and validate a methylation marker panel for triage of high-risk human papillomavirus (hr-HPV) positive patients. First, high-throughput quantitative methylation-specific PCRs (QMSP) on a novel OpenArraya platform, representing 424 primers of 213 cancer specific methylated genes, were performed on frozen tissue samples from 84 cervical cancer patients and 106 normal cervices. Second, the top 20 discriminating methylation markers were validated by LightCycle MSP on frozen tissue from 27 cervical cancer patients and 20 normal cervices and ROCs and test characteristics were assessed. Three new methylation markers were identified (JAM3, EPB41L3 and TERT), which were subsequently combined with C13ORF18 in our four-gene methylation panel. In a third step, our methylation panel detected in cervical scrapings 94% (70/74) of cervical cancers, while in a fourth step 82% (32/39) cervical intraepithelial neoplasia grade 3 or higher (CIN3+) and 65% (44/68) CIN2+ were detected, with 21% positive cases for ≤CIN1 (16/75). Finally, hypothetical scenario analysis showed that primary hr-HPV testing combined with our four-gene methylation panel as a triage test resulted in a higher identification of CIN3 and cervical cancers and a higher percentage of correct referrals compared to hr-HPV testing in combination with conventional cytology. In conclusion, our four-gene methylation panel might provide an alternative triage test after primary hr-HPV testing. © 2011 UICC.


Ohm J.E.,Johns Hopkins University | Ohm J.E.,University of North Dakota | Mali P.,Johns Hopkins University | Van Neste L.,Ghent University | And 20 more authors.
Cancer Research | Year: 2010

The ability to induce pluripotent stem cells from committed, somatic human cells provides tremendous potential for regenerative medicine. However, there is a defined neoplastic potential inherent to such reprogramming that must be understood and may provide a model for understanding key events in tumorigenesis. Using genome-wide assays, we identify cancer-related epigenetic abnormalities that arise early during reprogramming and persist in induced pluripotent stem cell (iPS) clones. These include hundreds of abnormal gene silencing events, patterns of aberrant responses to epigenetic-modifying drugs resembling those for cancer cells, and presence in iPS and partially reprogrammed cells of cancer-specific gene promoter DNA methylation alterations. Our findings suggest that by studying the process of induced reprogramming, we may gain significant insight into the origins of epigenetic gene silencing associated with human tumorigenesis, and add to means of assessing iPS for safety. ©2010 AACR.


Bosch L.J.W.,VU University Amsterdam | Mongera S.,VU University Amsterdam | Droste J.S.T.S.,VU University Amsterdam | Oort F.A.,VU University Amsterdam | And 7 more authors.
Cellular Oncology | Year: 2012

Background Stool-based molecular tests hold large potential for improving colorectal cancer screening. Here, we investigated the analytical sensitivity of a DNA methylation assay on partial stool samples, and estimated the DNA degradation in stool over time. In addition, we explored the detection ofDNA methylation in fecal immunochemical test (FIT) fluid. Materials and Methods Partial stool samples of colonoscopynegative individuals were homogenized with stool homogenization buffer, spiked with different numbers of HCT116 colon cancer cells and kept at room temperature for 0, 24, 48, 72 and 144 h before DNA isolation. Analytical sensitivity was determined by the lowest number of cells that yielded positive test results by DNA methylation ormutation analysis. DNA methylation in FIT fluid was measured in 11 CRC patients and 20 control subjects. Results The analytical sensitivity for detecting DNA methylation was 3000 cells per gram stool, compared to 60000 cells per gram stool for detection of DNA mutations in the same stool samples. No degradation up to 72 h was noted when a conservation buffer was used. DNA methylation was detected in 4/11 CRC FIT samples and in none of the 20 control FIT samples. Conclusions Methylation based stool DNA testing showed a high analytical sensitivity for tumor DNA in partial stool samples, which was hardly influenced by DNA degradation over time, provided an adequate buffer was used. The feasibility of detecting DNA methylation in FIT fluid demonstrates the opportunity to combine testing for occult blood with DNA methylation in the same collection device. © International Society for Cellular Oncology 2012.


van Neste L.,Ghent University | van Neste L.,Oncomethylome science SA | Herman J.G.,The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Schuebel K.E.,The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | And 6 more authors.
Current Bioinformatics | Year: 2010

Epigenetics has become a cornerstone of cancer research and is an increasingly important factor in the continuous efforts to try and unravel the biology of oncogenesis. Consequently the analyses of epigenetic data have evolved towards genome wide and high-throughput approaches, generating large data sets for which computational data mining is indispensable. Bioinformatics has proven to be useful and beneficial for a plethora of tasks, going beyond elemental data management, and is now crucial for adequate candidate gene selection, data integration, comparison and correlation as well as providing insights into cancer biology. Computational approaches are used even in routine tasks like primer design, since multiple layers of information can be incorporated into a more efficient and consistent strategy. Almost every analysis feeds back information into both the biology and the tools we use during these experiments. As the cancer epigenetics field evolves rapidly, the combination with bioinformatics will create a synergy that increases our insights into cancer biology rapidly. This review summarizes some of the frequently used bioinformatics tools in large-scale or nextgeneration analyses in epigenetics that would not have been possible without the use of well-conceived computational strategies. © 2010 Bentham Science Publishers Ltd.


Renard I.,OncoMethylome science SA | Joniau S.,Catholic University of Leuven | van Cleynenbreugel B.,Catholic University of Leuven | Collette C.,OncoMethylome science SA | And 12 more authors.
European Urology | Year: 2010

Background: Accumulating evidence suggests that DNA methylation markers could serve as sensitive and specific cancer biomarkers. Objective: To determine whether a panel of methylated genes would have the potential to identify primary bladder cancer (BCa) in voided urine samples. Design, setting, and participants: A pharmacologic unmasking reexpression analysis in BCa cell lines was initially undertaken to unveil candidate methylated genes, which were then evaluated in methylation-specific polymerase chain reaction (MSP) assays performed on DNA extracted from noncancerous and cancerous bladder tissues. The most frequently methylated genes in cancerous tissues, with 100% specificity, were retained for subsequent MSP analysis in DNA extracted from urine samples to build and validate a panel of potential methylated gene markers. Urine samples were prospectively collected at three urologic centres from patients with histologically proven BCa and processed for use in real-time MSP and cytologic analysis. Patients with nonmalignant urologic disorders were included as controls. Measurements: A urine sample was classified as valid when ≥10 copies of the gene encoding ß-actin were measured in the urine sediment genomic DNA. Sensitivity, specificity, and predictive values of the MSP and cytology tests were assessed and compared. Results and limitations: MSP assays performed on 466 of the 496 (94%) valid urine samples identified two genes, TWIST1 and NID2, that were frequently methylated in urine samples collected from BCa patients, including those with early-stage and low-grade disease. The sensitivity of this two-gene panel (90%) was significantly better than that of cytology (48%), with comparable specificity (93% and 96%, respectively). The positive predictive value and negative predictive value of the two-gene panel was 86% and 95%, respectively. Conclusions: Detection of the methylated TWIST1 and NID2 genes in urine sediments using MSP provides a highly (≥90%) sensitive and specific, noninvasive approach for detecting primary BCa. Trial registration: BlCa-001 study - EudraCt 2006-003303-40. © 2009 European Association of Urology.


van der Auwera I.,University of Antwerp | Yu W.,Johns Hopkins University | Suo L.,Johns Hopkins University | van Neste L.,Oncomethylome science SA | And 6 more authors.
PLoS ONE | Year: 2010

Background: Abnormal DNA methylation is well established for breast cancer and contributes to its progression by silencing tumor suppressor genes. DNA methylation profiling platforms might provide an alternative approach to expression microarrays for accurate breast tumor subtyping. We sought to determine whether the distinction of the inflammatory breast cancer (IBC) phenotype from the non-IBC phenotype by transcriptomics could be sustained by methylomics. Methodology/Principal Findings: We performed methylation profiling on a cohort of IBC (N = 19) and non-IBC (N = 43) samples using the Illumina Infinium Methylation Assay. These results were correlated with gene expression profiles. Methylation values allowed separation of breast tumor samples into high and low methylation groups. This separation was significantly related to DNMT3B mRNA levels. The high methylation group was enriched for breast tumor samples from patients with distant metastasis and poor prognosis, as predicted by the 70-gene prognostic signature. Furthermore, this tumor group tended to be enriched for IBC samples (54% vs. 24%) and samples with a high genomic grade index (67% vs. 38%). A set of 16 CpG loci (14 genes) correctly classified 97% of samples into the low or high methylation group. Differentially methylated genes appeared to be mainly related to focal adhesion, cytokine-cytokine receptor interactions, Wnt signaling pathway, chemokine signaling pathways and metabolic processes. Comparison of IBC with non-IBC led to the identification of only four differentially methylated genes (TJP3, MOGAT2, NTSR2 and AGT). A significant correlation between methylation values and gene expression was shown for 4,981 of 6,605 (75%) genes. Conclusions/Significance: A subset of clinical samples of breast cancer was characterized by high methylation levels, which coincided with increased DNMT3B expression. Furthermore, an association was observed with molecular signatures indicative of poor patient prognosis. The results of the current study also suggest that aberrant DNA methylation is not the main force driving the molecular biology of IBC. © 2010 Van der Auwera et al.


Patent
Oncomethylome science S.A. | Date: 2014-02-13

The present invention relates to methods and kits for identifying, diagnosing, prognosing, and monitoring cervical cancer. These methods include determining the methylation status or the expression levels of particular genes, or a combination thereof.


Accumulating evidence suggests that DNA methylation markers could serve as sensitive and specific cancer biomarkers.To determine whether a panel of methylated genes would have the potential to identify primary bladder cancer (BCa) in voided urine samples.A pharmacologic unmasking reexpression analysis in BCa cell lines was initially undertaken to unveil candidate methylated genes, which were then evaluated in methylation-specific polymerase chain reaction (MSP) assays performed on DNA extracted from noncancerous and cancerous bladder tissues. The most frequently methylated genes in cancerous tissues, with 100% specificity, were retained for subsequent MSP analysis in DNA extracted from urine samples to build and validate a panel of potential methylated gene markers. Urine samples were prospectively collected at three urologic centres from patients with histologically proven BCa and processed for use in real-time MSP and cytologic analysis. Patients with nonmalignant urologic disorders were included as controls.A urine sample was classified as valid when > or = 10 copies of the gene encoding -actin were measured in the urine sediment genomic DNA. Sensitivity, specificity, and predictive values of the MSP and cytology tests were assessed and compared.MSP assays performed on 466 of the 496 (94%) valid urine samples identified two genes, TWIST1 and NID2, that were frequently methylated in urine samples collected from BCa patients, including those with early-stage and low-grade disease. The sensitivity of this two-gene panel (90%) was significantly better than that of cytology (48%), with comparable specificity (93% and 96%, respectively). The positive predictive value and negative predictive value of the two-gene panel was 86% and 95%, respectively.Detection of the methylated TWIST1 and NID2 genes in urine sediments using MSP provides a highly (> or = 90%) sensitive and specific, noninvasive approach for detecting primary BCa.BlCa-001 study - EudraCt 2006-003303-40.

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