CAS Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institute of Nutrition and Health, Shanghai Institute for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai, 200031, China.
Medical Genomics Group, UCL Cancer Institute, University College London, 72 Huntley Street, WC1E 6BT, London, UK.
Nat Commun. 2024 May 17;15(1):4211. doi: 10.1038/s41467-024-48649-8.
The cumulative number of stem cell divisions in a tissue, known as mitotic age, is thought to be a major determinant of cancer-risk. Somatic mutational and DNA methylation (DNAm) clocks are promising tools to molecularly track mitotic age, yet their relationship is underexplored and their potential for cancer risk prediction in normal tissues remains to be demonstrated. Here we build and validate an improved pan-tissue DNAm counter of total mitotic age called stemTOC. We demonstrate that stemTOC's mitotic age proxy increases with the tumor cell-of-origin fraction in each of 15 cancer-types, in precancerous lesions, and in normal tissues exposed to major cancer risk factors. Extensive benchmarking against 6 other mitotic counters shows that stemTOC compares favorably, specially in the preinvasive and normal-tissue contexts. By cross-correlating stemTOC to two clock-like somatic mutational signatures, we confirm the mitotic-like nature of only one of these. Our data points towards DNAm as a promising molecular substrate for detecting mitotic-age increases in normal tissues and precancerous lesions, and hence for developing cancer-risk prediction strategies.
组织中的干细胞分裂次数，即有丝分裂年龄，被认为是癌症风险的主要决定因素。体细胞突变和 DNA 甲基化（DNAm）时钟是分子追踪有丝分裂年龄的有前途的工具，但它们之间的关系尚未得到充分探索，它们在正常组织中预测癌症风险的潜力仍有待证明。在这里，我们构建并验证了一种称为 stemTOC 的改进的泛组织 DNAm 计数器，用于总有丝分裂年龄。我们证明，stemTOC 的有丝分裂年龄代理在 15 种癌症类型中的每一种、癌前病变中和暴露于主要癌症风险因素的正常组织中，随肿瘤细胞起源分数的增加而增加。与其他 6 个有丝分裂计数器的广泛基准测试表明，stemTOC 表现良好，特别是在侵袭前和正常组织的背景下。通过将 stemTOC 与两个类似时钟的体细胞突变特征进行交叉相关，我们证实只有其中一个具有有丝分裂样性质。我们的数据表明，DNAm 是检测正常组织和癌前病变中有丝分裂年龄增加的有前途的分子基质，因此也是开发癌症风险预测策略的有前途的分子基质。
