• Joo Mi Yi, Mashaal Dhir, Leander Van Neste, Stephanie R Downing, Jana Jeschke, Sabine C Glöckner, Marilia de Freitas Calmon, Craig M Hooker, Juan M Funes, Chris Boshoff, Kim M Smits, Manon van Engeland, Matty P Weijenberg, Christine A Iacobuzio-Donahue, James G Herman, Kornel E Schuebel, Stephen B Baylin, and Nita Ahuja.
• Department of Oncology, Johns Hopkins University, Baltimore, Maryland 20892-8110, USA.
• Clin Cancer Res. 2011 Mar 15;17(6):1535-45.

PurposeThe importance of genetic and epigenetic alterations maybe in their aggregate role in altering core pathways in tumorigenesis.Experimental DesignMerging 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.ResultsWe 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 = 777). DNA methylation of IGFBP3 and EVL predicted for poor survival (IGFBP3: HR = 2.58, 95% CI: 1.37-4.87, P = 0.004; EVL: HR = 2.48, 95% CI: 1.07-5.74, P = 0.034) and simultaneous methylation of multiple genes predicted significantly worse survival (HR = 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 = 2.06, 95% CI: 1.04-4.09, P = 0.038; EVL HR = 2.23, 95% CI: 1.00-5.0, P = 0.05) and EVL DNA methylation remained significant in a secondary historical validation cohort (HR = 1.41, 95% CI: 1.05-1.89, P = 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 = 0.001 for simultaneous methylation of IGFBP3, EVL, and CD109).ConclusionsCRC 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.©2011 AACR.

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