Methylation of estrogen receptor α and mutL homolog 1 in normal colonic mucosa: association with folate and vitamin B-12 status in subjects with and without colorectal neoplasia

Abstract

Serum vitamin B-12 but not folate status may be associated with ERalpha promoter methylation in normal-appearing colorectal mucosa.

Profiling CpG island field methylation in both morphologically normal and neoplastic human colonic mucosa

“…However, it should be noted that in a recent study, Kawakami et al (2006) observed age-related increases in CGI methylation for some genes classified as Type C by Toyota et al, which argues against any such rigid classification. In the present study, we observed statistically significant age-related increases in CGI methylation for HPP1, p16, APC, AXIN2, SFRP1, SFRP2, SFRP4, N33 and DKK1, but contrary to previous studies (Issa et al, 1994;Kawakami et al, 2006;Al-Ghnaniem et al, 2007), the CGI methylation of ESR1, MYOD and MLH1 showed no correlation with age in our patients. These findings may be due to analytical differences resulting in different CpGs within each island analysed or may indicate that the rates and sites of CGI methylation differ between populations, perhaps because of genotypic variation (Kawakami et al, 2006) or differing exposure to environmental factors, such as diet (Al-Ghnaniem et al, 2007) or commensal microorganisms.…”

“…However, the average methylation levels were significantly higher in neoplasia-free subjects compared with cancer patients (Table 2) This observation suggests that epigenetic field changes may include both loss and gain of methylation. Our data for ESR1 contradict those of Al-Ghnaniem et al (2007) who reported that ESR1 was 19% more methylated in the normal mucosa of cancer patients than in those free of disease. The role of WIF1 in the Wnt signalling pathway is poorly understood.…”

“…In a comparison of patients with and without adenomas, the methylation of p16, MLH1 and MGMT could not predict the presence of adenoma (Ye et al, 2006); in colorectal cancer patients, significant methylation was observed at the surgical margin (p10 cm from tumour) and was shown to be influenced by gender and by a polymorphism in the DNMT3B gene (Shen et al, 2005;Kawakami et al, 2006;Zhang et al, 2006;Iacopetta et al, 2007). Other studies have examined hyperplastic polyposis, where extensive methylation may underlie the condition (Minoo et al, 2006), and neoplasia-free, adenoma, hyperplastic polyp and cancer patients, where ESR1 and MLH1 methylation were generally higher in subjects with neoplasia, and were negatively associated with vitamin B-12 status (Al-Ghnaniem et al, 2007). In the present study, we have extended the investigation of methylation events in the mucosal field by using a QMSP assay to measure CGI methylation in 18 genes selected from the literature for their involvement in colorectal neoplasia, and shown previously to be affected by aberrant CGI methylation.…”

Normal colorectal mucosa exhibits sex- and segment-specific susceptibility to DNA methylation at the hMLH1 and MGMT promoters

“…The main focus of our study was in fact the earlier-stage epigenetic alterations in hMLH1 and MGMT, which might be found before the onset of clinically evident colorectal tumorigenesis. Few attempts have been made to characterize epigenetic changes in these genes in tumor-free human colons, and in all of these studies, the analysis was limited to one segment (generally the rectum) (Shen et al, 2005;Ye et al, 2006;Al-Ghnaniem et al, 2007). In contrast, our study was pancolonic in scope and involved systematic, segment-by-segment, quantitative analysis of hMLH1 and MGMT promoter methylation.…”

DNA methylation within the normal colorectal mucosa is associated with pathway-specific predisposition to cancer

“…The results are mixed. Some have reported no association with pathology, others that patients with polyps have increased methylation within their colorectal field and two recent reports have even suggested an inverse association between the presence of colorectal neoplasia and background mucosal methylation (Ye et al, 2006;Al-Ghnaniem et al, 2007;Belshaw et al, 2008;Horii et al, 2008;Ally et al, 2009;Figueiredo et al, 2009;Menigatti et al, 2009). Reconciling these discrepant results is limited by nonstandardized mucosal sampling, the important confounders of age and region, the use of variable marker panels and techniques and that adenomas may not be an adequate pathological end point when evaluating methylation markers more closely associated with the CIMP pathway.…”