Background The phenomenon of field cancerization reflects the transition of normal cells into those predisposed to cancer. Assessing the scope and intensity of this process in the colon may support risk prediction and colorectal cancer prevention. Methods The SWEPIC study, encompassing 1,111 participants for DNA methylation analysis and a subset of 84 for RNA-seq, was employed to detect field cancerization in individuals with adenomatous polyps (AP). Methylation variations were evaluated for their discriminative capability, including in external cohorts, genomic localization, clinical correlations, and associated RNA expression patterns. Results Normal cecal tissue of individuals harboring an AP in the proximal colon manifested dysregulated DNA methylation compared to tissue from healthy individuals at 558 unique loci. Leveraging these adenoma-related differentially variable and methylated CpGs (aDVMCs), our classifier discerned between healthy and AP-adjacent tissues across SWEPIC datasets (cross-validated ROC AUC [0.63-0.81]), including within age-stratified cohorts. This discriminative capacity was validated in three external sets, differentiating healthy from cancer-adjacent tissue (ROC AUC: [0.82-0.88]). Notably, aDVMC dysregulation correlated with polyp multiplicity. More than 50% of aDVMCs were significantly associated with age. These aDVMCs were enriched in active regions of the genome (p < .001), and associated genes exhibited altered expression in AP-adjacent tissues. Conclusions Our findings underscore the early onset of field cancerization in the right colon during the neoplastic transformation process. A more extensive validation of aDVMC dysregulation as a stratification tool could pave the way for enhanced surveillance approaches, especially given its linkage to adenoma emergence.

中文翻译：

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正常粘膜中的 DNA 甲基化变异：腺瘤性息肉患者的现场癌化标志物

背景 局部癌化现象反映了正常细胞向易患癌症的细胞的转变。评估结肠中这一过程的范围和强度可能有助于风险预测和结直肠癌预防。方法 SWEPIC 研究包括 1,111 名参与者进行 DNA 甲基化分析和 84 名参与者进行 RNA 测序，用于检测腺瘤性息肉 (AP) 个体的现场癌化情况。评估了甲基化变异的判别能力，包括外部队列、基因组定位、临床相关性和相关 RNA 表达模式。结果 与健康个体的组织相比，近端结肠中携带 AP 的个体的正常盲肠组织在 558 个独特位点表现出 DNA 甲基化失调。利用这些与腺瘤相关的差异变异和甲基化 CpG (aDVMC)，我们的分类器在 SWEPIC 数据集中区分健康组织和 AP 邻近组织（交叉验证的 ROC AUC [0.63-0.81]），包括在年龄分层队列中。这种区分能力在三个外部组中得到验证，区分健康组织和癌旁组织（ROC AUC：[0.82-0.88]）。值得注意的是，aDVMC 失调与息肉多重性相关。超过 50% 的 aDVMC 与年龄显着相关。这些 aDVMC 在基因组的活性区域富集 (p < .001)，并且相关基因在 AP 邻近组织中表现出表达改变。结论 我们的研究结果强调了在肿瘤转化过程中右结肠早期发生癌变。对 aDVMC 失调作为分层工具进行更广泛的验证可以为加强监测方法铺平道路，特别是考虑到它与腺瘤出现的联系。