TY - JOUR
T1 - Predicting clinical outcome of 5-fluorouracil-based chemotherapy for colon cancer patients: is the CpG island methylator phenotype the 5-fluorouracil-responsive subgroup?
AU - Iacopetta, Barry
AU - Kawakami, K.
AU - Watanabe, T.
PY - 2008
Y1 - 2008
N2 - 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.
AB - 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.
U2 - 10.1007/s10147-008-0854-3
DO - 10.1007/s10147-008-0854-3
M3 - Article
C2 - 19093176
VL - 13
SP - 498
EP - 503
JO - International Journal of Clinical Oncology
JF - International Journal of Clinical Oncology
SN - 1341-9625
IS - 6
ER -