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Genomic and Epigenomic Integration Identifies a Prognostic Signature in Colon Cancer

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... Full description

Journal Title: Clinical Cancer Research 2011, Vol.17(6), pp.1535-1545
Main Author: Yi, Joo Mi
Other Authors: Dhir, Mashaal , Van Neste, Leander , Downing, Stephanie R. , Jeschke, Jana , Gloeckner, Sabine C. , Calmon, Marilia de Freitas , Hooker, Craig M. , Funes, Juan M. , Boshoff, Chris , Smits, Kim M. , van Engeland, Manon , Weijenberg, Matty P. , Iacobuzio-Donahue, Christine A. , Herman, James G. , Schuebel, Kornel E. , Baylin, Stephen B. , Ahuja, Nita
Format: Electronic Article Electronic Article
Language: English
Subjects:
ID: ISSN: ; ISSN: 1078-0432
Link: https://cris.maastrichtuniversity.nl/portal/en/publications/genomic-and-epigenomic-integration-identifies-a-prognostic-signature-in-colon-cancer(fcd138c5-2574-4a96-b262-0222bc7a8aae).html
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recordid: narcisum:oai:cris.maastrichtuniversity.nl:publications/fcd138c5-2574-4a96-b262-0222bc7a8aae
title: Genomic and Epigenomic Integration Identifies a Prognostic Signature in Colon Cancer
format: Article
creator:
  • Yi, Joo Mi
  • Dhir, Mashaal
  • Van Neste, Leander
  • Downing, Stephanie R.
  • Jeschke, Jana
  • Gloeckner, Sabine C.
  • Calmon, Marilia de Freitas
  • Hooker, Craig M.
  • Funes, Juan M.
  • Boshoff, Chris
  • Smits, Kim M.
  • van Engeland, Manon
  • Weijenberg, Matty P.
  • Iacobuzio-Donahue, Christine A.
  • Herman, James G.
  • Schuebel, Kornel E.
  • Baylin, Stephen B.
  • Ahuja, Nita
subjects:
  • Medicine
ispartof: Clinical Cancer Research, 2011, Vol.17(6), pp.1535-1545
description: 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 = 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).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.
language: eng
source:
identifier: ISSN: ; ISSN: 1078-0432
fulltext: fulltext
issn:
  • 1078-0432
  • 1557-3265
url: Link


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titleGenomic and Epigenomic Integration Identifies a Prognostic Signature in Colon Cancer
creatorYi, Joo Mi ; Dhir, Mashaal ; Van Neste, Leander ; Downing, Stephanie R. ; Jeschke, Jana ; Gloeckner, Sabine C. ; Calmon, Marilia de Freitas ; Hooker, Craig M. ; Funes, Juan M. ; Boshoff, Chris ; Smits, Kim M. ; van Engeland, Manon ; Weijenberg, Matty P. ; Iacobuzio-Donahue, Christine A. ; Herman, James G. ; Schuebel, Kornel E. ; Baylin, Stephen B. ; Ahuja, Nita
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ispartofClinical Cancer Research, 2011, Vol.17(6), pp.1535-1545
identifierISSN: ; ISSN: 1078-0432
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descriptionPURPOSE: 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 = 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).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.
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