Purpose Pancreatic cancer is the fourth leading cause of cancer deaths and there currently is no reliable modality for the early detection of this disease. Here we identify cancer-specific promoter DNA methylation of BNC1 and ADAMTS1 as a promising biomarker detection strategy meriting investigation in pancreatic cancer. Experimental Design We used a genome-wide pharmacologic transcriptome approach to identify novel cancer-specific DNA methylation alterations in pancreatic cancer cell lines. Of 8 promising genes, we focused our studies on BNC1 and ADAMTS1 for further downstream analysis including methylation and expression. We used a nanoparticle-enabled MOB (Methylation On Beads) technology to detect early stage pancreatic cancers by analyzing DNA methylation in patient serum. Results We identified 2 novel genes, BNC1 (92%) and ADAMTS1, (68%) that showed a high frequency of methylation in pancreas cancers (n=143), up to 100% in PanIN-3 and 97% in Stage I invasive cancers. Using the nanoparticle-enabled MOB technology, these alterations could be detected in serum samples (n=42) from pancreas cancer patients, with a sensitivity for BNC1 of 79% (95%CI:66-91%) and for ADAMTS1 of 48% (95%CI:33-63%), while specificity was 89% for BNC1 (95%CI:76-100%) and 92% for ADAMTS1 (95%CI:82-100%). Overall sensitivity using both markers is 81% (95%CI:69-93%) and specificity is 85% (95%CI:71-99%). Conclusions Promoter DNA methylation of BNC1 and ADAMTS1 are potential biomarkers to detect early stage pancreatic cancers. Assaying the promoter methylation status of these genes in circulating DNA from serum is a promising strategy for early detection of pancreatic cancer and has the potential to improve mortality from this disease.
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.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.