Smoking is associated with hypermethylation of the APC 1A promoter in colorectal cancer: the ColoCare Study

Abstract

Smoking tobacco is a known risk factor for the development of colorectal cancer, and for mortality associated with the disease. Smoking has been reported to be associated with changes in DNA methylation in blood and in lung tumour tissues, although there has been scant investigation of how epigenetic factors may be implicated in the increased risk of developing colorectal cancer. To identify epigenetic changes associated with smoking behaviours, we performed epigenome-wide analysis of DNA methylation in colorectal tumours from 36 never smokers, 47 former smokers and 13 active smokers, and adjacent mucosa from 49 never smokers, 64 former smokers and 18 active smokers. Our analyses identified 15 CpG sites within the APC 1A promoter that were significantly hypermethylated and 14 CpG loci within the NFATC1 gene body that were significantly hypomethylated (pLIS<1×10−5) in tumours of active smokers. The APC 1A promoter was hypermethylated in 7 of 36 tumours from never smokers (19%), 12 of 47 tumours from former smokers (26%), and 8 of 13 tumours from active smokers (62%). Promoter hypermethylation was positively associated with duration of smoking (Spearman rank correlation, ρ=0.26, p=0.03) and was confined to tumours, with hypermethylation never being observed in adjacent mucosa. Further analysis of adjacent mucosa revealed significant hypomethylation of four loci associated with the TNXB gene in tissue from active smokers. Our findings provide exploratory evidence for hypermethylation of the key tumour suppressor gene APC being implicated in smoking-associated colorectal carcinogenesis. Further work is required to establish the validity of our observations in independent cohorts.

Robust prediction of gene regulation in colorectal cancer tissues from DNA methylation profiles

“…To study the methylation-gene expression relationships, we obtained matching DNA methylation and gene expression data from 77 colorectal cancer (CRC) and 108 adjacent mucosa tissues (Supplementary Table 1) from the ColoCare Study [ 19 ]. Adjacent mucosa samples are referred to “normal”; however, they may be affected by molecular crosstalk from cancer cells through activation of pro-tumorigenic functions [ 23 ].…”

“…We utilized DNA methylation and matching gene expression data from the ColoCare cohort [ 19 ], including samples taken from CRC tissues and normal tissues of adjacent mucosa, to investigate the regulatory role of DNA methylation on CRC gene expression. We show that gene regulation between CRC and normal tissues can be robustly predicted from DNA methylation differences for a subset of genes, which is enriched in common cancer pathways.…”

Genome-wide DNA methylation profiles of low- and high-grade adenoma reveals potential biomarkers for early detection of colorectal carcinoma

“…To ensure consistency of data processing, we only compared our samples with publically accessible samples with raw idat files. GSE68060, GSE68838, GSE77954, GSE77965, GSE81211, GSE101764, GSE107352, and GSE75546 were collected from GEO while E-MTAB-6450 was collected from ArrayExpress [43][44][45][46][47][48] (Additional file 1: Table S6). Some cell line samples and metastatic cancer samples were removed upon further study.…”

Methylation and Expression of Nonclustered Protocadherins Encoding Genes and Risk of Precancerous Gastric Lesions in a High-Risk Population

“…ORs with corresponding 95% confidence intervals (CI) were calculated by unconditional logistic regression to evaluate the association of DNA methylation with major characteristics. These characteristics have been associated with progression of gastric lesions and risk of gastric cancer previously (21,25,26) and may change methylation status based on current literature (27,28) and our prior research (7). Participants were classified into hypermethylation (median or higher) and hypomethylation (lower than median) groups for each gene.…”