Adverse prognostic effect of methylation in colorectal cancer is reversed by microsatellite instability.
OBJECTIVE
DNA methylation is an important biologic event in colorectal cancer and in some cases is associated with the development of microsatellite instability (MSI). In this study, we sought to determine the prognostic significance of DNA methylation, both in univariate analysis and in concert with other clinicopathologic factors known to influence outcome.


METHODS
Fresh tissue (625 cancers) was obtained from 605 individuals (age range, 29 to 99 years) undergoing curative surgery for colorectal cancer at one institution during a period of 8 years. Clinicopathologic details were recorded for all tumors, including stage, grade, type, vascular space invasion, and clinical follow-up to 5 years. Microsatellite status was assessed using standard markers. Methylation of p16 and hMLH1 promoters was determined by methylation-specific polymerase chain reaction (PCR), whereas methylation at methylated-in-tumor loci (MINT)1, MINT2, MINT12, and MINT31 loci were assessed by bisulfite-PCR.


RESULTS
Patients with microsatellite unstable tumors (12%) had better disease-specific survival than those with microsatellite stable (MSS) tumors (univariate analysis: hazard ratio [HR], 0.53; 95% CI, 0.27 to 1.0). Overall survival of individuals with MSS tumors was influenced by three independently significant factors: tumor stage (HR, 7.3; 95% CI, 5.1 to 10.4), heavy tumor methylation (HR, 2.1; 95% CI, 1.1 to 4.0), and vascular space invasion (HR, 1.9; 95% CI, 1.3 to 2.9). In MSS tumors, methylation at any single site was not independently predictive of survival. Neither methylation nor microsatellite status predicted a favorable response to chemotherapy.


CONCLUSIONS
DNA methylation is associated with a worse outcome in colorectal cancer, but this adverse prognostic influence is lost in those methylated tumors showing MSI. The mechanisms of these events warrant additional investigation.
Ward
Robyn Lynne
RL
Department of Medical Oncology and Colorectal Surgery, St Vincent's Hospital, Darlinghurst, Australia. r.ward@garvan.unsw.edu.au
Cheong
Kay
K
Ku
Su-Lyn
SL
Meagher
Alan
A
O'Connor
Terence
T
Hawkins
Nicholas John
NJ
D000328:Adult; D000368:Aged; D015179:Colorectal Neoplasms / Q000235:genetics*; D004249:DNA Damage; D019175:DNA Methylation; D004273:DNA, Neoplasm; D005260:Female; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D011379:Prognosis; D015996:Survival Rate; D016896:Treatment Outcome
D004273:DNA, Neoplasm