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 (CH(2)FH(4)) occur in CIMP+
tumors and are probably due to low expression levels for
gamma-glutamyl hydrolase (GGH). Clinical and in vitro work has previously shown that high CH(2)FH(4) 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.