Implications of epigenetic drift in colorectal neoplasia

Many normal tissues undergo age-related DNA methylation drift providing a quantitative measure of tissue age. However this drift has not been demonstrated in neoplastic tissues. Here we identify and validate 781 CpG-islands (CGIs) that undergo significant methylomic drift in normal colorectal tissues continue to drift in neoplasia and remain significantly correlated with one another across tissue samples. However compared with normal colon this drift advances (~3-4 fold) faster in neoplasia consistent with increased cell proliferation during neoplastic progression. Furthermore we show that the observed drift patterns are broadly consistent with modeled adenoma-carcinoma sojourn time distributions from colorectal cancer (CRC) incidence data. These results support the hypothesis that beginning with the founder premalignant cell cancer precursors frequently sojourn for decades before turning into cancer which implies that the founder cell typically arises early in life. We estimate that at least 77-89% of the observed drift variance in distal and rectal tumors is explained by stochastic variability associated with neoplastic progression while only 55% of the variance is explained for proximal tumors. However >50% of identified gene-CGI pairs in the proximal colon that undergo drift are significantly and mainly negatively correlated with cancer gene expression suggesting that methylomic drift participates in the clonal evolution of CRCs. Significance: Methylomic drift advances in colorectal neoplasia consistent with extended sojourn time distributions explaining a significant fraction of epigenetic heterogeneity in CRCs. Importantly the estimated long-duration premalignant sojourn times suggest that early dietary and lifestyle interventions may be more effective than later changes in reducing CRC incidence. We evaluated methylation levels at CpG probes using the Illumina HM450 beadchip array (HM450) in a total of 675 colorectal tissue samples. Of particular interest were site and sex differences in methylomic drift inter-individual heterogeneity and whether drift patterns at the probe and CGI level reflect the expected variance of tissue sojourn times in the adenoma-to-carcinoma sequence.