Abstract
BackgroundTwo molecular pathways promote the development of colorectal cancer (CRC). One is termed “microsatellite stable” (MSS) whereas the other is characterized by “microsatellite instability” (MSI or MIN). In addition, the CpG island methylation phenotype is known to be an important alteration as a third molecular type. Thus, DNA methylation is thought to provide potential biomarkers for assessment of cancer risk in normal mucosa. In addition, it is also known that colonic location is an important parameter in the development of CRC.MethodsWe examined the surrounding normal mucosa in three parts of the colon. Next, we quantified DNA methylation levels of SFRP1, SFRP2, SFRP5, DKK2, DKK3, mir34b/c, RASSF1A, IGFBP7, CDKN2A, and MLH1 in isolated cancerous glands and crypts of normal colorectal mucosa adjacent to CRCs using a pyrosequencer.ResultsDNA methylation levels of SFRP1, SFRP2, DKK2, and mir34b/c were significantly higher in CRCs with an MSS phenotype than in those with an MSI phenotype. The average level of methylation in normal crypts did not decrease with the distance from the tumor, irrespective of microsatellite status or the tumor location. DNA methylation levels in SFRP1 and SFRP2 genes in normal crypts were significantly higher in left-side than right-side CRC with an MSS phenotype. Finally, the genes were classified into three types based on the methylation frequencies in normal crypts, including type I (SFRP1 and SFRP2I), type II (DKK2 and mir34b/c), and type III (others).ConclusionsOur results showed that DNA methylation of SFRP1 and SFRP2 might be useful to predict cancer risk of surrounding normal mucosa. In addition, a field effect may be present in CRC, affecting both adjacent and non-adjacent normal mucosa.
Highlights
Two molecular pathways promote the development of colorectal cancer (CRC)
DNA methylation levels in cancerous crypts compared to surrounding normal crypts based on microsatellite instability (MSI) status We examined DNA methylation levels of SFRP1, SFRP2, SFRP5, DKK2, DKK3, mir34b/c, RASSF1A, Insulin growth factor-binding protein 7 (IGFBP7), Cyclin-dependent kinase inhibitor 2A (CDKN2A), and Mut L homolog 1 (MLH1) genes in cancerous crypts isolated from microsatellite stable” (MSS) and MSI CRCs
We examined differences in DNA methylation between cancerous crypts from CRC and normal crypts isolated from the surrounding normal mucosa based on MSS and MSI status
Summary
Two molecular pathways promote the development of colorectal cancer (CRC). One is termed “microsatellite stable” (MSS) whereas the other is characterized by “microsatellite instability” (MSI or MIN). Colorectal cancer (CRC) develops via accumulation of numerous genetic and epigenetic alterations, as normal colorectal epithelium transforms into an adenoma, progresses to cancer [1, 2]. New classification systems have been proposed based on comparisons of gene expression levels in tumor cells with those in corresponding normal cell populations (stem-like, inflammatory, transit-amplifying, goblet-like cells and enterocytes). These molecular classifications are useful to elucidate colorectal carcinogenesis, dichotomization of molecular classification (e.g., MSS and MSI) has been useful in that dichotomization shows mutually exclusive phenomena
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