Aberrant methylation of APC, MGMT, RASSF2A, and Wif-1 genes in plasma as a biomarker for early detection of colorectal cancer.
OBJECTIVE
To identify epigenetic molecular makers in plasma for the early detection of colorectal cancer.


METHODS
We retrospectively analyzed the methylation status of 10 genes in fresh-frozen tissues and corresponding plasma samples from 243 patients with stage I and II sporadic colorectal cancer, 276 healthy individuals, and plasma from 64 colorectal adenoma patients using methylation-specific PCR. The methylation score (Mscore) was used to find molecular markers with high sensitivity and specificity.


RESULTS
Of the 243 colorectal cancer tissues, methylation was detected in 18% for p14, 34% for p16, 27% for APC, 34% for DAPK, 32% for HLTF, 21% for hMLH1, 39% for MGMT, 24% for RARbeta2, 58% for RASSF2A, and 74% for Wif-1. Receiver operator characteristic curve analysis in plasma from 243 patients with cancer and 276 healthy individuals showed that the M score of any single gene had a sensitivity of <40% after controlling for age, sex, and tumor location. The specificity of the M score was not different between multigene and single gene analyses, but the sensitivity of the M score was significantly increased by multigene analysis. For all patients, the M score in a model including APC, MGMT, RASSF2A, and Wif-1 genes had a sensitivity of 86.5% and a specificity of 92.1% when 1.6 was used as a cutoff. In this model, the M score had a positive predictive value of 90.6% and a negative predictive value of 88.8%.


CONCLUSIONS
The present study suggests that tumor-specific methylation of APC, MGMT, RASSF2A, and Wif-1 genes might be a valuable biomarker in plasma for the early detection of colorectal cancer.
Molecular Cell Biology, Samsung Medical Center, Seoul, Korea.
Bo Bin
BB
Lee
Eun Ju
EJ
Lee
Eun Hyun
EH
Jung
Ho-Kyung
HK
Chun
Dong Kyoung
DK
Chang
Sang Yong
SY
Song
Joobae
J
Park
Duk-Hwan
DH
Kim
D048868:Adaptor Proteins, Signal Transducing / Q000097:blood* / Q000235:genetics; D000236:Adenoma / Q000097:blood / Q000175:diagnosis* / Q000235:genetics; D000368:Aged; D014408:Biomarkers, Tumor / Q000097:blood* / Q000235:genetics; D015179:Colorectal Neoplasms / Q000097:blood / Q000175:diagnosis* / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics; D015254:DNA Modification Methylases / Q000097:blood* / Q000235:genetics; D045643:DNA Repair Enzymes / Q000097:blood* / Q000235:genetics; D055088:Early Detection of Cancer / Q000379:methods; D005260:Female; D017491:Genes, APC; D006801:Humans; D008297:Male; D008875:Middle Aged; D010949:Plasma / Q000378:metabolism; D020033:Protein Isoforms / Q000097:blood / Q000235:genetics; D012097:Repressor Proteins / Q000097:blood* / Q000235:genetics; D012189:Retrospective Studies; D025521:Tumor Suppressor Proteins / Q000097:blood* / Q000235:genetics
D048868:Adaptor Proteins, Signal Transducing; D014408:Biomarkers, Tumor; D020033:Protein Isoforms; C425300:RASSF2 protein, human; D012097:Repressor Proteins; D025521:Tumor Suppressor Proteins; C485569:WIF1 protein, human; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D045643:DNA Repair Enzymes