Implications of Epigenetic Drift in Colorectal Neoplasia.
Implications of Epigenetic Drift in Colorectal Neoplasia.
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DOI：
10.1158/0008-5472.can-18-1682
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发表时间：
2019-02-01
期刊：
影响因子：
11.2
通讯作者：
Grady WM
中科院分区：
文献类型：
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作者：
Luebeck GE;Hazelton WD;Curtius K;Maden SK;Yu M;Carter KT;Burke W;Lampe PD;Li CI;Ulrich CM;Newcomb PA;Westerhoff M;Kaz AM;Luo Y;Inadomi JM;Grady WM
许多正常组织经历DNA甲基化的年龄相关漂移，提供组织年龄的定量测量。在这里，我们确定并验证了781个CpG岛（CGI），在232个正常结直肠组织中发生显著的甲基化漂移，并表明这些CGI在肿瘤形成中继续漂移，同时保持样本间的显著相关性。然而，与正常结肠相比，这种漂移在肿瘤形成中进展得更快（约3-4倍），与肿瘤进展期间细胞增殖增加一致。观察到的漂移模式与结直肠癌（CRC）发病率数据中的腺瘤-癌逗留时间分布模型大致一致。这些结果支持了这样的假设，即从创始人癌前细胞开始，癌症前体在转变为癌症之前经常逗留数十年，这意味着创始人细胞通常在生命早期出现。在远端和直肠肿瘤中观察到的漂移方差中至少有77-89%是由与肿瘤进展相关的随机变异性解释的，而近端肿瘤中只有55%的方差是由随机变异性解释的。然而，近端结肠中经历漂移的基因-CGI对与癌症基因表达显著且主要呈负相关，表明甲基化漂移参与了CRC的克隆进化。结直肠肿瘤中甲基化漂移的进展与延长的逗留时间分布一致，这是结直肠癌表观遗传异质性的一个重要部分。重要的是，这些估计的长期癌前逗留时间表明，早期饮食和生活方式的干预可能比以后的变化更有效地降低CRC的发病率。
Many normal tissues undergo age-related drift in DNA methylation, providing a quantitative measure of tissue age. Here we identify and validate 781 CpG-islands (CGI) that undergo significant methylomic drift in 232 normal colorectal tissues and show that these CGI continue to drift in neoplasia while retaining significant correlations across samples. However, compared with normal colon, this drift advanced (~3–4 fold) faster in neoplasia, consistent with increased cell proliferation during neoplastic progression. The observed drift patterns were 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, implying that the founder cell typically arises early in life. At least 77–89% of the observed drift variance in distal and rectal tumors was explained by stochastic variability associated with neoplastic progression, while only 55% of the variance was explained for proximal tumors. However, gene-CGI pairs in the proximal colon that underwent drift were significantly and primarily negatively correlated with cancer gene expression, suggesting that methylomic drift participates in the clonal evolution of CRC. Methylomic drift advanced in colorectal neoplasia consistent with extended sojourn time distributions, which accounts for a significant fraction of epigenetic heterogeneity in CRC. Importantly, these estimated long-duration premalignant sojourn times suggest that early dietary and lifestyle interventions may be more effective than later changes in reducing CRC incidence.