Colorectal cancer risk in bowel adenomas based on lifestyle exposures, tissue preconditioning and DNA methylation

BackgroundColorectal cancer (CRC) is associated with patient demographics, lifestyle exposures and molecular alterations. However, it is not possible to determine which adenomas will progress to CRC, as ethically it is unacceptable to leave and follow adenomas. We hypothesised that certain lifestyle exposures at high levels could precondition exposed bowel tissue by changing and aging it, increasing the risks of deleterious DNA methylation and genetic alterations. We used a novel study design comparing adenomas with concurrent CRC (thus more likely exposed to deleterious lifestyle effects) to single adenomas in bowels with no history of CRC; we called these high (HR) and low-risk (LR) adenomas respectively. MethodsWe carried out a discovery and replication epigenome-wide association study (EWAS) on 106 HR and 111 LR adenomas, profiled with MethylationEPIC BeadChips. In order, to identify differentially methylated positions (DMP), regions (DMR), and DNAm (DNAmethylation) lifestyle exposures and risks, with adjustment for confounders, and gene ontology (GO) and pathway enrichment. Then, two open-source gene expression omnibus (GEO) validation datasets (52, 57 and 49, 48 HR and LR normal bowel tissues respectively) were analysed for these DNAm lifestyle exposures and risks, with adjustment for confounders. ResultsOur EWAS found 5 Bonferroni significant DMPs with absolute delta betas [≥] 5%, and 14 significant DMRs with absolute mean DMR delta betas [≥] 5%, replicated in the GPX7, RGS3 and TMEM135 cancer-associated genes. DNAm high alcohol exposures were strongly associated with increased risk of HR adenomas (odds ratio (OR) per standard deviation (SD) = 2.16 (95% confidence interval (CI) 1.55 - 3.09, p-value = 9.7 x 10-6)). In the validation datasets, DNAm high alcohol (ORperSD = 2.12 (95% CI 1.35 - 3.55, p-value = 2.0 x 10-3) and ORperSD = 1.79 (95% CI 1.14 - 2.96, p-value = 1.7 x 10-2)), and high body mass index (BMI) exposures (ORperSD = 1.72 (95% CI 1.13 - 2.73, p-value = 1.5 x 10-2)) were associated with increased risk of HR normal bowel tissues. ConclusionsHigh alcohol and BMI exposures may precondition normal bowel tissues and adenomas for increased risk of DNA methylation alterations associated with CRC progression. The DNAm exposure signatures and our newly identified genes may be useful epigenetic biomarkers for CRC prevention.