The role of the CpG island methylator phenotype in colorectal cancer prognosis depends on microsatellite instability screening status.
OBJECTIVE
The aim of this study was to relate the CpG island methylator phenotype (CIMP; characterized by extensive promoter hypermethylation) to cancer-specific survival in colorectal cancer, taking into consideration relevant clinicopathologic factors, such as microsatellite instability (MSI) screening status and the BRAF V600E mutation.


METHODS
Archival tumor samples from 190 patients from the Northern Sweden Health and Disease Study (NSHDS) and 414 patients from the Colorectal Cancer in Umeå Study (CRUMS), including 574 with cancer-specific survival data, were analyzed for an eight-gene CIMP panel using quantitative real-time PCR (MethyLight). MSI screening status was assessed by immunohistochemistry.


RESULTS
CIMP-low patients had a shorter cancer-specific survival compared with CIMP-negative patients (multivariate hazard ratio in NSHDS, 2.01; 95% confidence interval, 1.20-3.37; multivariate hazard ratio in CRUMS, 1.48; 95% confidence interval, 1.00-2.22). This result was similar in subgroups based on MSI screening status and was statistically significant in microsatellite stable (MSS) tumors in NSHDS. For CIMP-high patients, a shorter cancer-specific survival compared with CIMP-negative patients was observed in the MSS subgroup. Statistical significance was lost after adjusting for the BRAF mutation, but the main findings were generally unaffected.


CONCLUSIONS
In this study, we found a poor prognosis in CIMP-low patients regardless of MSI screening status, and in CIMP-high patients with MSS. Although not consistently statistically significant, these results were consistent in two separate patient groups and emphasize the potential importance of CIMP and MSI status in colorectal cancer research.
Dahlin
Anna M
AM
Department of Medical Biosciences, Pathology, and Department of Surgical and Perioperative Sciences, Surgery, Umeå University, Umeå, Sweden. anna.dahlin@medbio.umu.se
Palmqvist
Richard
R
Henriksson
Maria L
ML
Jacobsson
Maria
M
Eklöf
Vincy
V
Rutegård
Jörgen
J
Oberg
Ake
A
Van Guelpen
Bethany R
BR
D000328:Adult; D000368:Aged; D015179:Colorectal Neoplasms / Q000235:genetics*; D018899:CpG Islands / Q000235:genetics*; D019175:DNA Methylation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D010641:Phenotype; D011379:Prognosis; D011401:Promoter Regions, Genetic; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D015996:Survival Rate
C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf