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

DNA methylation within the normal colorectal mucosa is associated with pathway-specific predisposition to cancer,10.1038/onc.2009.449,Oncogene,D L Wor

DNA methylation within the normal colorectal mucosa is associated with pathway-specific predisposition to cancer   (Citations: 7)
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D L Worthley, V L J Whitehall, R L Buttenshaw, N Irahara, S A Greco, I Ramsnes, K-A Mallitt, R K Le Leu, J Winter, Y Hu, S Ogino, G P Younghttp://academic.research.microsoft.com/io.ashx?type=5&id=28181612&selfId1=0&selfId2=0&maxNumber=12&query=
Journal: Oncogene , vol. 29, no. 11, pp. 1653-1662, 2010
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    • ...DNA methylation gradient for ESR1, HIC1, HPP1, SFRP1 and MINT2 in a series of 166 patients [10]...
    • ...We hypothesized, however, that a continuous luminal or epithelial factor would provide a better explanation for the incremental epigenetic gradient that we, and others, have observed [9, 10]...
    • ...the normal-appearing mucosa may reflect pathological predispositions throughout the colorectum [10]...
    • ...In our recent colonoscopic study of DNA methylation, we found an inverse association between background mucosal ‘‘type A’’ methylation and the presence of colorectal adenomas, the pathological precursors to the CIN-pathway [10]...
    • ...There was, however, a direct association between CIMP methylation in the background mucosa and concomitant proximal serrated polyps, precursors to CIMP pathway CRC [10]...
    • ...The ‘‘type A’’ and ‘‘type C’’ gene classifications were based on earlier work from other groups and, in particular, from our own observations regarding the relationship between patient age and levels of locus-specific DNA methylation within the normal colorectal mucosa [5, 7, 10, 25, 26]...
    • ... genes (ESR1, GATA5, HIC1, HPP1, SFRP1) and the 5 CIMP panel genes (IGF2, NEUROG1, CACNA1G, RUNX3, SOCS1 )[ 8] were calculated according to their distribution (Z-score = PMR value - mean PMR)/standard deviation) and then the Z-scores averaged across each 5 marker panel (‘‘type A’’ Z-score = (Z(ESR1) ? Z(GATA5) ? Z(HIC1) ? Z(HPP1) ? Z(SFRP1))/5 and CIMP Zscore = (Z(CACNA1G) ? Z(IGF2) ? Z(NEUROG1) ? Z(SOCS1) ? Z(RUNX3))/5), as described [10, ...
    • ...‘‘Type A’’ methylation was detected in the normal rectal mucosa of all patients but, as expected [10], ‘‘type C’’ markers exhibited much lower levels of methylation (Table 1)...
    • ... with ‘‘high’’ compared to ‘‘low’’ fecal total SCFA (Table 1). The same was true for subjects with ‘‘low’’ compared to ‘‘high’’ fecal pH (Table 1), albeit that the relationship between ‘‘type A’’ methylation markers and fecal butyrate concentrations was more mixed (supplementary Table 3). The proximal colon is characterized by high SCFA and low pH, and these markers, generally, have lower levels of methylation in the proximal colon [10]...
    • ...DNA methylation in the normal colorectal mucosa is likely to be influenced by environmental factors such as smoking [10], genetics, age and also complex pathological predispositions such as hyperplastic polyposis syndrome and ulcerative colitis [7, 9, 31]...
    • ...Luminal pH, influenced by SCFA concentrations, shows the reciprocal gradient, with the proximal colonic lumen exhibiting the lowest pH. In a recent study, ESR1, HIC1, HPP1, SFRP1, MINT2, all demonstrated an impressive methylation gradient with the highest methylation found in the rectum, followed sequentially by the sigmoid, transverse colon and cecum [10]...
    • ... lower fecal SCFA concentrations and higher fecal pH (Table 2). Furthermore, the mean ‘‘type A’’ methylation Z-score was associated with a borderline inverse association with total fecal SCFA concentrations on multivariate linear regression (Table 3). This suggested that higher luminal concentrations of SCFA may be involved in establishing the observed colorectal gradient, albeit that these results must be confirmed by larger studies [10]...
    • ...Whilst, patients with colorectal adenomas do not appear to have significantly greater demethylation of LINE-1 in their normal colorectal mucosa [10, 32], patients with CRC may have greater LINE-1 demethylation in their resected, peritumoral normal mucosa [23]...
    • ...There was a significant, direct correlation between DNA methylation of ESR1 and GATA5 and crypt proliferation (Fig. 2). There was also a significant, independent and direct association between mean ‘‘type A’’ methylation Z-score and rectal proliferation on multivariate linear regression (supplementary Table 4). In light of the strong correlation that has been demonstrated between ‘‘type A’’ methylation and age in other studies [9, 10], it ...
    • ...Greater proliferation and ‘‘tissue age’’ may be important in the development of ‘‘type A’’ methylation found almost uniformly in carcinomas, with ‘‘type A’’ methylation possibly a consequence, rather than a cause of, carcinogenesis [10, 38]...
    • ...Interestingly, once controlled for age, ‘‘type A’’ methylation within the background colorectal mucosa is inversely associated with colorectal neoplasia [10]...
    • ...This suggests that background mucosal ‘‘type A’’ methylation is not a critical factor in the development of an at-risk CRC field [10]...

    Daniel L. Worthleyet al. DNA Methylation in the Rectal Mucosa Is Associated with Crypt Prolifer...

    • ... Some studies have established that epigenetic alterations could be indicators of field cancerization in the colon...

    Victoria Valinluck Laoet al. Epigenetics and colorectal cancer

    • ...In contrast to cancerspecific methylation markers, recent studies have indicated that aging-related DNA methylation markers tend to decrease in their methylation levels in normal colon mucosa from adenoma or cancer patients than in normal mucosa from tumor-free subjects [38, 39]...
    • ...However, unlike hypomethylation in aging-related methylation markers, LINE-1 hypomethylation has been demonstrated to be not associated with concomitant pathology [38, 40]...

    Hyeong-Ju Kwonet al. DNA methylation changes in ex-adenoma carcinoma of the large intestine

    • ...This is supported by our DNA methylation data in other “type A” genes [23]...
    • ...Furthermore, as demonstrated in a recent study, [23]THBS4 behaved as a “type A” marker with respect to its association with neoplasia found elsewhere within the field...

    Sonia A Grecoet al. Thrombospondin4 is a putative tumour-suppressor gene in colorectal can...

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