CpG island methylation as an early event during adenoma progression in carcinogenesis of sporadic colorectal cancer.
OBJECTIVE
CpG island methylation is present in various tumors, including colorectal carcinomas, and is thought to be an important mechanism in carcinogenesis. We evaluated the methylation status of primary colorectal tumors to determine its role in the adenoma to carcinoma sequence.


METHODS
The methylation status of APC, THBS1, MGMT, hMLH1 and GSTP1, as determined by methylation specific PCR (MSP), and microsatellite instability (MSI) using three mononucleotide markers were assessed in 40 colorectal adenomas and 36 adenocarcinomas. The correlations of methylation status and MSI with the clinicopathologic parameters of the tumors were determined.


RESULTS
Of the 40 adenomas, 24 (60%) were methylated at one or more loci, and 12 (30%) at two or more loci (CpG island methylation phenotype-high, CIMP-H). Of 36 carcinomas, 27 (75%) were methylated at one or more loci and 11 (30.5%) at two or more loci (CIMP-H). THBSI was the most frequently methylated locus in both adenomas (n = 19, 47.5%) and carcinomas (n = 16, 44.4%). Overall, methylation status of adenomas and carcinomas did not differ significantly (P = 0.53), nor did the methylation status of individual genes. For adenomas, size (P = 0.049) and histologic classification of the villous components (P = 0.018) were each associated with methylation status. For carcinomas, however, no clinicopathologic variable was related to methylation status. MSI was detected in three adenomas (7.5%) and five carcinomas (13.9%), and was closely correlated with hMLH1 methylation (P < 0.001).


CONCLUSIONS
In colorectal tumors, CpG island methylation of tumor suppressor genes appears to be common and may be involved in the progression of adenomas.
Kim
Hee Cheol
HC
Department of Surgery, University of Ulsan College of Medicine and Asan Medical Center, Seoul, Korea. hckim@amc.seoul.kr
Roh
Sun Ae
SA
Ga
In Hwa
IH
Kim
Jung-Sun
JS
Yu
Chang Sik
CS
Kim
Jin Cheon
JC
D000230:Adenocarcinoma / Q000235:genetics*; D000236:Adenoma / Q000235:genetics*; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D016009:Chi-Square Distribution; D015179:Colorectal Neoplasms / Q000235:genetics*; D018899:CpG Islands / Q000235:genetics*; D019175:DNA Methylation; D005260:Female; D006801:Humans; D016014:Linear Models; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction