Virchows Archiv

, Volume 450, Issue 5, pp 529–537

CpG island methylation, response to combination chemotherapy, and patient survival in advanced microsatellite stable colorectal carcinoma

  • Shuji Ogino
  • Jeffrey A. Meyerhardt
  • Takako Kawasaki
  • Jeffrey W. Clark
  • David P. Ryan
  • Matthew H. Kulke
  • Peter C. Enzinger
  • Brian M. Wolpin
  • Massimo Loda
  • Charles S. Fuchs
Original Article

DOI: 10.1007/s00428-007-0398-3

Cite this article as:
Ogino, S., Meyerhardt, J.A., Kawasaki, T. et al. Virchows Arch (2007) 450: 529. doi:10.1007/s00428-007-0398-3

Abstract

The CpG island methylator phenotype (CIMP) is a distinct epigenetic phenotype in colorectal carcinoma with concordant methylation in multiple promoter CpG islands. The relationship between CpG island methylation and clinical outcomes among colorectal cancer patients treated with chemotherapy has been a controversial subject. Utilizing real-time polymerase chain reaction (PCR; MethyLight technology), we quantified DNA methylation in 13 CpG island loci (CACNA1G, CDKN2A, CRABP1, IGF2, MLH1, NEUROG1, RUNX3, SOCS1, MINT1, MINT31, IGFBP3, MGMT, and WRN) in 30 metastatic microsatellite stable colorectal carcinomas in phase I/II clinical trials of combination chemotherapy (5-fluorouracil, irinotecan, leucovorin, and gefitinib). Tumor response was assessed by CT scans performed at baseline and every 6 weeks thereafter. Overall CIMP-high status (either ≥9/13 or ≥7/13 methylated markers; identifying 3 or 5 CIMP-high tumors, respectively) and methylation in CACNA1G, IGF2, MLH1, NEUROG1, RUNX3, MINT31, and WRN were associated with worse survival (all p < 0.01). Although not statistically significant, there was a trend toward resistance to chemotherapy among tumors with CpG island methylation. In conclusion, CpG island methylation may predict poor survival in metastatic microsatellite stable colorectal carcinoma treated with chemotherapy. Additional studies are necessary to examine the role of DNA methylation in treatment efficacy.

Keywords

Colon cancer CIMP DNA methylation Epigenetics Chemotherapy 

Abbreviations and HUGO Gene Nomenclature Committee (HGNC)-approved official gene symbols

CACNA1G

calcium channel, voltage-dependent, T-type alpha-1G subunit

CDKN2A

cyclin-dependent kinase inhibitor 2A (p16/INK4A)

CIMP

CpG island methylator phenotype

CRABP1

cellular retinoic acid binding protein 1

5-FU

5-fluorouracil

IGF2

insulin-like growth factor 2

IGFBP3

insulin-like growth factor binding protein 3

MGMT

O-6-methylguanine-DNA methyltransferase

MINT1

methylated in tumor 1

MINT31

methylated in tumor 31

MSI

microsatellite instability

MSS

microsatellite stable

NEUROG1

neurogenin 1

PMR

percentage of methylated reference (degree of DNA methylation)

RUNX3

runt-related transcription factor 3

SOCS1

suppressor of cytokine signaling 1

WRN

Werner syndrome gene

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Shuji Ogino
    • 1
    • 2
    • 3
  • Jeffrey A. Meyerhardt
    • 3
    • 4
    • 5
  • Takako Kawasaki
    • 3
  • Jeffrey W. Clark
    • 5
    • 6
  • David P. Ryan
    • 5
    • 6
  • Matthew H. Kulke
    • 3
    • 4
    • 5
  • Peter C. Enzinger
    • 3
    • 4
    • 5
  • Brian M. Wolpin
    • 3
    • 4
    • 5
  • Massimo Loda
    • 1
    • 2
    • 3
  • Charles S. Fuchs
    • 3
    • 4
    • 5
  1. 1.Department of Pathology, Brigham and Women’s HospitalHarvard Medical SchoolBostonUSA
  2. 2.Department of PathologyHarvard Medical SchoolBostonUSA
  3. 3.Department of Medical OncologyDana-Farber Cancer InstituteBostonUSA
  4. 4.Department of MedicineBrigham and Women’s HospitalBostonUSA
  5. 5.Department of MedicineHarvard Medical SchoolBostonUSA
  6. 6.Department of MedicineMassachusetts General HospitalBostonUSA

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