Background: Colorectal cancer (CRC) is characterized by the uncontrolled growth of malignant colonic or rectal crypt epithelium. About 85% of CRCs evolve through a stepwise progression from advanced precancerous adenoma lesions. A better understanding of the evolution from adenoma to carcinoma can provide a window of opportunity not only for early detection and therapeutic intervention but potentially also for cancer prevention strategies.Methods: This study investigates the heterogeneous methylation, copy-number alteration (CNA), and mutation signals of histological adenoma subtypes in the context of progression from normal colon to advanced precancerous lesions (APLs) and early-stage CRC.Results: Differential methylation analysis revealed 2321 significantly altered regions among APLs: 137 hypermethylated regions in serrated vs. tubular, 2093 in serrated vs. tubulovillous, and 91 in tubular vs. tubulovillous adenoma subtypes. The most differentiating pathways for serrated adenomas belonged to cAMP signaling and the regulation of pluripotency of stem cells, while regions separating tubular and tubulovillous subtypes were enriched for WNT signaling. CNA events were mostly present in tubular or tubulovillous adenomas, with the most frequent signals being seen in chromosomes 7, 12, 19, and 20. In contrast, early-stage CRC exhibited signals in chromosomes 7, 8, and 20, indicating different processes between APL and early-stage CRC. Mutations reinforce subtype-level differences, showing specific alterations in each subtype.Conclusions: These findings are especially important for developing early detection or cancer prevention tests trying to capture adenoma signatures.
背景：结直肠癌（CRC）的特征是恶性结肠或直肠隐窝上皮的失控性生长。约85%的结直肠癌经由晚期癌前腺瘤病变的逐步进展演变而来。深入理解从腺瘤到癌的演变过程，不仅为早期检测和治疗干预提供机会窗口，也可能为癌症预防策略开辟新途径。 方法：本研究在从正常结肠进展至晚期癌前病变（APLs）及早期结直肠癌的背景下，探究了组织学腺瘤亚型的异质性甲基化、拷贝数变异（CNA）及突变信号。 结果：差异甲基化分析揭示了晚期癌前病变中存在2321个显著改变区域：锯齿状腺瘤与管状腺瘤相比有137个高甲基化区域，与管状绒毛状腺瘤相比有2093个，而管状与管状绒毛状腺瘤亚型间存在91个差异区域。锯齿状腺瘤最具区分度的通路涉及cAMP信号传导和干细胞多能性调控，而区分管状与管状绒毛状亚型的区域则富集于WNT信号通路。拷贝数变异事件主要存在于管状或管状绒毛状腺瘤中，最常见信号见于7、12、19和20号染色体。相比之下，早期结直肠癌在7、8和20号染色体表现出信号，提示晚期癌前病变与早期结直肠癌存在不同的演进过程。突变分析进一步强化了亚型层面的差异，显示出各亚型特有的基因改变。 结论：这些发现对于开发旨在捕获腺瘤特征的早期检测或癌症预防检测方法具有特别重要的意义。
肿瘤(癌症)患者之家