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Predicting clinical outcome of 5-fluorouracil-based chemotherapy for colon cancer patients: is the CpG island methylator phenotype the 5-fluorouracilresponsive subgroup?

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Abstract

The CpG island methylator phenotype (CIMP+) of colorectal cancer (CRC) occurs predominantly in the proximal colon and is characterized by frequent hypermethylation of gene promoter regions. In this review, we present evidence suggesting CIMP+ represents the subgroup of colon cancers that are responsive to 5-fluorouracil (5-FU)-based treatments. CIMP+ has been associated with survival benefit from 5-FU in a clinical study of CRC, with additional evidence coming from studies on gastric cancer and tumor cell lines. Elevated concentrations of 5-10-methylene tetrahydrofolate (CH2FH4) occur in CIMP+ tumors and are probably due to low expression levels for γ-glutamyl hydrolase (GGH). Clinical and in vitro work has previously shown that high CH2FH4 and low GGH expression levels correlate with good response to 5-FU. Methylation-induced silencing of dihydropyrimidine dehydrogenase, the rate-limiting enzyme in 5-FU degradation, may also provide a link between CIMP+ and good response to 5-FU. The CIMP+-related phenotype referred to as microsatellite instability (MSI+) has been widely investigated as a predictive marker of response to 5-FU, with contradictory results. The interpretation of these studies is likely to be confounded by the fact that some MSI+ tumors occur in the background of CIMP+, but a significant proportion of others do not. Further studies on tumors from randomized clinical trials are required to confirm the value of CIMP+ and associated molecular features for the prediction of clinical outcome to 5-FU-based chemotherapy.

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Authors and Affiliations

  1. School of Surgery M507, University of Western Australia, 35 Stirling Highway, Nedlands, 6009, Australia

    Barry Iacopetta

  2. Division of Translational and Clinical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa, Japan

    Kazuyuki Kawakami

  3. Department of Surgery, Teikyo University School of Medicine, Tokyo, Japan

    Toshiaki Watanabe

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  1. Barry Iacopetta
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  2. Kazuyuki Kawakami
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  3. Toshiaki Watanabe
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Correspondence to Barry Iacopetta.

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Iacopetta, B., Kawakami, K. & Watanabe, T. Predicting clinical outcome of 5-fluorouracil-based chemotherapy for colon cancer patients: is the CpG island methylator phenotype the 5-fluorouracilresponsive subgroup?. Int J Clin Oncol 13, 498–503 (2008). https://doi.org/10.1007/s10147-008-0854-3

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