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Updated: Aug 24, 2026

Genome-Wide Analysis of DNA Methylation in Gastrointestinal Cancer
Published on: September 18, 2020
Aberrant CpG island hypermethylation of multiple genes in colorectal neoplasia
Sun Lee1, Kyu Sang Hwang, Hyeon Joo Lee
1Department of Pathology, National Cancer Center, Goyang, Gyeonggi, Korea.
Abstract:
CpG island hypermethylation is a potential means of inactivating tumor suppressor genes, and many genes have been demonstrated to be hypermethylated and silenced in colorectal cancer. However, limited data is available upon the concurrent methylation of multiple genes in colorectal cancer and in its precursor lesion. To address changes in the methylation profiles of multiple genes during colorectal carcinogenesis, we investigated the methylation of 12 genes (APC, COX-2, DAP-kinase, E-cadherin, GSTP1, hMLH1, MGMT, p14, p16, RASSF1A, THBS1, and TIMP3) in normal colon (n=24), colon adenoma (n=95), and colorectal cancer (n=149), using methylation-specific PCR. The average number of these genes methylated per sample was 0.12, 1.8, and 3.0 in normal colon mucosa, adenoma, and carcinoma, respectively, showing a stepwise increase (P<0.001). All the genes were methylated in colorectal cancer at frequencies varying from 51 to 9.4% and colon adenoma displayed methylation for the 11 genes, except for GSTP1, at frequencies varying from 40 to 1.1%. In contrast, normal colon mucosa demonstrated methylation for APC only, at a frequency of 12.5%. The total number of methylated genes per tumor showed a continuous, nonbimodal distribution in colon adenoma or cancer. CpG island hypermethylation exhibited a proclivity toward proximal colon cancer or adenoma, and the average number of genes methylated was higher in proximal colon cancer or adenoma than in distal colon cancer or adenoma, respectively (3.5 vs 2.6, P=0.018 for cancer, and 2.5 vs 1.4, P=0.003 for adenoma). In conclusion, concurrent CpG island methylation is an early and frequent event during colorectal carcinogenesis. It appears that CpG island methylation plays a more important role in proximal colon cancer development than in distal colon cancer development.
Insights
CpG island hypermethylation is an early event in colorectal cancer development, with increasing gene methylation observed from normal tissue to adenoma and carcinoma. This epigenetic silencing is more prevalent in proximal colon cancers.
Area of Science:
- Molecular biology
- Cancer epigenetics
- Gastroenterology
Background:
- CpG island hypermethylation silences tumor suppressor genes in colorectal cancer.
- Limited data exists on concurrent methylation of multiple genes in colorectal cancer and precursor lesions.
Purpose of the Study:
- To investigate concurrent methylation profiles of 12 genes during colorectal carcinogenesis.
- To analyze methylation changes in normal colon, adenoma, and carcinoma.
Main Methods:
- Methylation-specific PCR was used to analyze 12 specific genes.
- Samples included normal colon (n=24), colon adenoma (n=95), and colorectal cancer (n=149).
Main Results:
- The average number of methylated genes increased stepwise from normal (0.12) to adenoma (1.8) to cancer (3.0).
- All 12 genes showed methylation in cancer; 11 genes (except GSTP1) in adenoma; only APC in normal colon.
- Hypermethylation was more frequent in proximal colon cancer and adenoma compared to distal counterparts.
Conclusions:
- Concurrent CpG island methylation is an early and frequent event in colorectal carcinogenesis.
- CpG island methylation appears more critical in proximal than distal colon cancer development.
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