CpG island methylator phenotype is an independent predictor of survival benefit from 5-fluorouracil in stage III colorectal cancer.
OBJECTIVE
The CpG island methylator phenotype (CIMP) is observed in approximately 30% of colorectal cancer (CRC) cases and is characterized by the concurrent methylation of multiple CpG islands in tumor DNA. This phenotype (CIMP+) is more frequently observed in tumors with proximal location, microsatellite instability, and normal p53. Because it has previously been observed that each of these features is associated with a good survival benefit from 5-fluorouracil (5-FU)-based adjuvant chemotherapy, we investigated in the present study whether CIMP+ has independent predictive value.


METHODS
CIMP+ status was evaluated in 103 stage III CRCs from patients treated with surgery alone and for an additional 103 cases from patients treated with surgery and adjuvant 5-FU-based chemotherapy. The two cohorts were randomly pair-matched for age, sex, and tumor site, and the median length of follow-up time was 39 months.


RESULTS
CIMP+ status predicted survival benefit from 5-FU treatment independently of microsatellite instability and p53 mutation status (relative risk = 0.22; 95% confidence interval, 0.06-0.84; P = 0.027). Unmeasured, high-risk confounding factors could only account for this association if they were unequally distributed between the two patient cohorts by a factor of at least 2-fold.


CONCLUSIONS
CIMP+ has independent predictive significance for the survival benefit from 5-FU chemotherapy in CRC. This molecular marker should be incorporated into prospective clinical trials of fluorouracil-based therapies to confirm its clinical value.
Van Rijnsoever
Marius
M
Departments of Surgery, University of Western Australia, Nedlands 6907, Australia.
Elsaleh
Hany
H
Joseph
David
D
McCaul
Kieran
K
Iacopetta
Barry
B
D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality*; D018899:CpG Islands; D019175:DNA Methylation; D043243:DNA Sequence, Unstable; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use*; D016158:Genes, p53; D006801:Humans; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009154:Mutation; D009369:Neoplasms / Q000378:metabolism; D010641:Phenotype; D011379:Prognosis; D012680:Sensitivity and Specificity; D013997:Time Factors
D000964:Antimetabolites, Antineoplastic; D005472:Fluorouracil