Abstract CN04-02: DNA methylation markers for colorectal cancer diagnosis
Authors: Mori Yuriko 
Published: May 2012

In the United States, colorectal cancer (CRC) is the third most prevalent and deadly malignancy. CRC is highly curable at the early stage. Five year survival rate is 90% for localized CRC but is less than 10% for CRCs with distant metastasis. Unfortunately, approximately two thirds of CRC cases are detected at advanced stages. The delayed diagnosis is due to the asymptomatic nature of early stage CRCs. Thus, the key to reduce the CRC death is comprehensive CRC screening for the average-risk population. A colonoscopy is the current gold standard for CRC detection, yet not ideal for comprehensive average-risk population surveillance due to its invasiveness and limited throughput. An emerging noninvasive and high-throughput approach is to detect CRC cell-derived DNA within body fluids and/or excretions by utilizing various DNA biomarkers. The utility (i.e., sensitivity, specificity, and throughput) of a CRC detection approach is ultimately defined by the quality of its biomarkers. Therefore, selecting the optimal DNA biomarkers for CRC detection is vitally important. Locus-specific DNA hypermethylation is a DNA abnormality linked to CRC. CRC-specific DNA hypermethylation possesses several merits as a bodily fluid/excretion-based CRC detection biomarker. Firstly, DNA hypermethylation starts from early colon tumorigenesis, which is beneficial for early stage CRC detection. Secondly, DNA hypermethylation is the gain of abnormal molecules, which is easier to detect than the absence of normal molecules (e.g., chromosomal deletion). Thirdly, only one assay per locus is necessary, unlike genetic mutation that often possesses multiple hotspots within a gene. Finally, multiple high-throughput quantitative assays for locus-specific DNA methylation are available and capable of analyzing low-integrity source DNAs. Recent advances in assay methodologies, markers, and published feasibility studies for DNA hypermethylation marker-based CRC detection will be discussed.

The majority of known hypermethylation targets linked to CRCs do not possess the optimal methylation profiles for CRC screening, because they were identified based upon their functional relevance to neoplastic progression, rather than their merit as the markers. Therefore, a systematic search for novel CRC-specific DNA hypermethylation based upon their merit as the markers is beneficial in advancing the development of optimal population-based CRC screening methodologies. Recent technical advances enabled the direct, genome-wide, and high-resolution assessment of locus-specific DNA hypermethylation that is crucial for this type of systematic search. Within this context, we conducted a genome-wide screen for loci that were hypermethylated in primary sporadic CRCs relative to normal colonic mucosae (NCM) obtained from non-neoplastic control cases who were older than 50 years of age at the time of sampling. DNA microarrays, coupled with methylated CpG island amplification, were employed for this screen. This microarray analysis surveyed approximately half of all CpG islands and CpGrich gene promoter regions within the genome. The outcome of this genomewide screen will also be discussed.

Citation Information: Cancer Prev Res 2010;3(1 Suppl):CN04-02.