Genomic and Epigenomic Integration Identifies a Prognostic Signature in Colon Cancer

Department of Oncology, Johns Hopkins University, Baltimore, Maryland 20892-8110, USA.
Clinical Cancer Research (Impact Factor: 8.72). 03/2011; 17(6):1535-45. DOI: 10.1158/1078-0432.CCR-10-2509
Source: PubMed


The importance of genetic and epigenetic alterations maybe in their aggregate role in altering core pathways in tumorigenesis.
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.
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 = 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).
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.

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    • "Tumor suppressor. DAPK1 functions as a positive mediator of apoptosis induced by various other stimuli [Deiss et al., 1995; Bialik and Kimchi , 2006] Hypermethylation: lung [Toyooka et al., 2003], gastric [Chan et al., 2005], breast [Lehmann et al., 2002] cancers EVL Ena/VASP like protein Actin-associated proteins , extra-cellular matrix genes Strengthens cell-to-cell interaction [Bournier et al., 2006] EVL hypermethylation in all poorly differentiated tumors suggests that it is a factor in cell invasiveness [Bournier et al., 2006] Hypermethylation: colorectal cancer [Mokarram et al., 2009; Yi et al., 2011] 14.3.3 Phospho-serine/-threonine binding proteins Regulation of cell differentiation, proliferation and transformation [Qi et al., 2005] Hypermethylation: lung [Qi et al., 2005], breast [Ferguson et al., 2000], liver [Iwata et al., 2000] cancers. "
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