Aberrant Methylation ofAPC, MGMT, RASSF2A, andWif-1Genes in Plasma as a Biomarker for Early Detection of Colorectal Cancer

Abstract

Purpose: To identify epigenetic molecular makers in plasma for the early detection of colorectal cancer. Experimental Design: 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 (M score) 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 RARβ2, 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%. Conclusion: 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. (Clin Cancer Res 2009;15(19):6185-91)

Analysis of APC and IGFBP7 promoter gene methylation in Swedish and Vietnamese colorectal cancer patients

“…The reported methylation status of the promoter of APC varies greatly among studies of CRC in different populations (16)(17)(18)(19)(20). Moreover, hypermethylation of the APC promoter has been shown to be relatively common in other gastrointestinal neoplasms, including those of the stomach, liver, pancreas and oesophagus (17,29).…”

“…The APC promoter methylation rate has been detected in CRC and normal colorectal mucosa at a range of 11 to 62% in different populations, and has been suggested to moderate the Wnt signalling pathway (16)(17)(18)(19)(20). Studies have indicated that IGFBP7 is inactivated by DNA methylation in human colon, lung and breast cancer (21)(22)(23).…”

Effects of irradiation on radioresistance, HOTAIR and epithelial-mesenchymal transition/cancer stem cell marker expression in esophageal squamous cell carcinoma

“…The Wnt signaling pathway is crucial for stem cell survival, proliferation, differentiation, and chemo-/radioresistance (37,38) due to the action of Wnt inhibitory factor 1 (WIF-1), a critical inhibitor of the Wnt signaling pathway (39). Several studies have demonstrated that aberrant activation of the Wnt signaling pathway due to genetic and epigenetic alterations occurs in several types of cancer (39)(40)(41)(42).…”

Promoter methylation of WNT inhibitory factor-1 and expression pattern of WNT/β-catenin pathway in human astrocytoma: pathologic and prognostic correlations

“…WIF1 is known to be downregulated in many malignant tumors such as hepatocellular carcinoma, 11,12 nasopharyngeal carcinoma, 13,14 lung cancer, 9,15 colon cancer, 14 renal cell carcinoma, 16 esophageal adenocarcinoma, 17 melanoma, 18 and bladder cancer. 19 The main mechanism of WIF1 inactivation is aberrant promoter methylation, as demonstrated by the inverse correlation between WIF1 promoter methylation and expression of WIF1 mRNA or protein 8,11,12,[19][20][21][22][23][24] and restoration of WIF1 expression by promoter demethylation treatment.…”

“…Several authors support the theory that promoter methylation occurs in the early stage of carcinogenesis based on the observation that genes of nonneoplastic tissue from organs containing tumor are more frequently methylated than those of tissue from patients without tumor. 14,17,24 However, studies on the methylation status of nonneoplastic tissue adjacent to tumors of various organs revealed controversial results. It has been reported that WIF1 promoter hypermethylation is more frequent in adjacent normal colorectal mucosa from cancer patients compared with normal mucosa from patients without tumor.…”