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

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.

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Fig. 1

Abbreviations

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

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Acknowledgment

This work was partly supported by the United States National Institute of Health (NIH) grants P01 CA87969-03 and P01 CA55075-13. We deeply thank the patients who participated in the clinical trials, and Ann L. Michelini and Kate Kinsella for their assistance in the management of the clinical trials. This study complied with the current laws of the USA.

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Correspondence to Shuji Ogino.

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Ogino, S., Meyerhardt, J.A., Kawasaki, T. et al. CpG island methylation, response to combination chemotherapy, and patient survival in advanced microsatellite stable colorectal carcinoma. Virchows Arch 450, 529–537 (2007). https://doi.org/10.1007/s00428-007-0398-3

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Keywords

  • Colon cancer
  • CIMP
  • DNA methylation
  • Epigenetics
  • Chemotherapy