Evaluation of markers for CpG island methylator phenotype (CIMP) in colorectal cancer by a large population-based sample.
The CpG island methylator phenotype (CIMP or CIMP-high) with extensive promoter methylation is a distinct phenotype in colorectal cancer. However, a choice of markers for CIMP has been controversial. A recent extensive investigation has selected five methylation markers (CACNA1G, IGF2, NEUROG1, RUNX3, and SOCS1) as surrogate markers for epigenomic aberrations in tumor. The use of these markers as a CIMP-specific panel needs to be validated by an independent, large dataset. Using MethyLight assays on 920 colorectal cancers from two large prospective cohort studies, we quantified DNA methylation in eight CIMP-specific markers [the above five plus CDKN2A (p16), CRABP1, and MLH1]. A CIMP-high cutoff was set at > or = 6/8 or > or = 5/8 methylated promoters, based on tumor distribution and BRAF/KRAS mutation frequencies. All but two very specific markers [MLH1 (98% specific) and SOCS1 (93% specific)] demonstrated > or = 85% sensitivity and > or = 80% specificity, indicating overall good concordance in methylation patterns and good performance of these markers. Based on sensitivity, specificity, and false positives and negatives, the eight markers were ranked in order as: RUNX3, CACNA1G, IGF2, MLH1, NEUROG1, CRABP1, SOCS1, and CDKN2A. In conclusion, a panel of markers including at least RUNX3, CACNA1G, IGF2, and MLH1 can serve as a sensitive and specific marker panel for CIMP-high.
Ogino
Shuji
S
Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. shuji_ogino@dfci.harvard.edu
Kawasaki
Takako
T
Kirkner
Gregory J
GJ
Kraft
Peter
P
Loda
Massimo
M
Fuchs
Charles S
CS
D048868:Adaptor Proteins, Signal Transducing / Q000032:analysis / Q000235:genetics; D014408:Biomarkers, Tumor / Q000032:analysis*; D020747:Calcium Channels, T-Type / Q000032:analysis / Q000235:genetics; D002277:Carcinoma / Q000175:diagnosis* / Q000235:genetics* / Q000473:pathology; D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000175:diagnosis* / Q000235:genetics* / Q000473:pathology; D050677:Core Binding Factor Alpha 3 Subunit / Q000032:analysis / Q000235:genetics; D018899:CpG Islands; D019175:DNA Methylation; D005260:Female; D005500:Follow-Up Studies; D005820:Genetic Testing / Q000379:methods; D005828:Genetics, Population; D006801:Humans; D007335:Insulin-Like Growth Factor II; D008297:Male; D000070957:MutL Protein Homolog 1; D009687:Nuclear Proteins / Q000032:analysis / Q000235:genetics; D010641:Phenotype; D011401:Promoter Regions, Genetic; D011506:Proteins / Q000032:analysis / Q000235:genetics; D012680:Sensitivity and Specificity
D048868:Adaptor Proteins, Signal Transducing; D014408:Biomarkers, Tumor; C121855:CACNA1G protein, human; D020747:Calcium Channels, T-Type; D050677:Core Binding Factor Alpha 3 Subunit; C035170:IGF2 protein, human; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D011506:Proteins; C493729:Runx3 protein, human; D007335:Insulin-Like Growth Factor II; D000070957:MutL Protein Homolog 1