Background & Aims
Genetic and epigenetic alterations contribute to the pathogenesis of
colorectal cancer (CRC). There is considerable molecular heterogeneity among
colorectal tumors, which appears to arise as polyps progress to cancer. This
heterogeneity results in different pathways to tumorigenesis. Although
epigenetic and genetic alterations have been detected in conventional
tubular adenomas, little is known about how these affect progression to CRC.
We compared methylomes of normal colon mucosa, tubular adenomas, and
colorectal cancers to determine how epigenetic alterations might contribute
to cancer formation.
Methods
We conducted genome-wide array-based studies and comprehensive data
analyses of aberrantly methylated loci in 41 normal colon tissue, 42 colon
adenomas, and 64 cancers using HumanMethylation450 arrays.
Results
We found genome-wide alterations in DNA methylation in the non-tumor
colon mucosa adjacent to tubular adenomas and cancers. Three classes of
cancers and 2 classes of adenomas were identified based on their DNA
methylation patterns. The adenomas separated into classes of high-frequency
methylation (adenoma-H), and low-frequency methylation (adenoma-L). Within
the adenoma-H class a subset of adenomas had mutant KRAS.
Additionally, the adenoma-H class had DNA methylation signatures similar to
those of cancers with low or intermediate levels of methylation, whereas the
adenoma-L class had methylation signatures similar to that of non-tumor
colon tissue. The CpGs sites that were differentially methylated in these
signatures are located in intragenic and intergenic regions.
Conclusions
Genome-wide alterations in DNA methylation occur during early stages
of progression of tubular adenomas to cancer. These findings reveal
heterogeneity in the pathogenesis of colorectal cancer, even at the adenoma
step of the process.
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