Quantitative analysis of methylation of genomic loci in early-stage rectal cancer predicts distant recurrence.
OBJECTIVE
There are no accurate prognostic biomarkers specific for rectal cancer. Epigenetic aberrations, in the form of DNA methylation, accumulate early during rectal tumor formation. In a preliminary study, we investigated absolute quantitative methylation changes associated with tumor progression of rectal tissue at multiple genomic methylated-in-tumor (MINT) loci sequences. We then explored in a different clinical patient group whether these epigenetic changes could be correlated with clinical outcome.


METHODS
Absolute quantitative assessment of methylated alleles was used to assay methylation changes at MINT 1, 2, 3, 12, 17, 25, and 31 in sets of normal, adenomatous, and malignant tissues from 46 patients with rectal cancer. Methylation levels of these biomarkers were then assessed in operative specimens of 251 patients who underwent total mesorectal excision (TME) without neoadjuvant radiotherapy in a multicenter clinical trial.


RESULTS
Methylation at MINT 2, 3, and 31 increased 11-fold (P = .005), 15-fold (P < .001), and two-fold (P = .02), respectively, during adenomatous transformation in normal rectal epithelium. Unsupervised grouping analyses of quantitative MINT methylation data of TME trial patients demonstrated two prognostic subclasses. In multivariate analysis of node-negative patients, this subclassification was the only predictor for distant recurrence (hazard ratio [HR], 4.17; 95% CI, 1.72 to 10.10; P = .002), cancer-specific survival (HR, 3.74; 95% CI, 1.4 to 9.43; P = .003), and overall survival (HR, 2.68; 95% CI, 1.41 to 5.11; P = .005).


CONCLUSIONS
Methylation levels of specific MINT loci can be used as prognostic variables in patients with American Joint Committee on Cancer stage I and II rectal cancer. Quantitative epigenetic classification of rectal cancer merits evaluation as a stratification factor for adjuvant treatment in early disease.
de Maat
Michiel F G
MF
Department of Molecular Oncology, John Wayne Cancer Institute, 2200 Santa Monica Blvd, Santa Monica, CA 90404, USA.
van de Velde
Cornelis J H
CJ
van der Werff
Martijn P J
MP
Putter
Hein
H
Umetani
Naoyuki
N
Klein-Kranenbarg
Elma Meershoek
EM
Turner
Roderick R
RR
van Krieken
J Han J M
JH
Bilchik
Anton
A
Tollenaar
Rob A E M
RA
Hoon
Dave S B
DS
D000236:Adenoma / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D019175:DNA Methylation; D018450:Disease Progression; D006801:Humans; D005810:Multigene Family; D009367:Neoplasm Staging; D011379:Prognosis; D012004:Rectal Neoplasms / Q000235:genetics* / Q000473:pathology / Q000601:surgery