Department of Pathology, Yale School of Medicine, New Haven, CT, USA.
San Diego Institute of Science, Altos Labs, San Diego, CA, USA.
Sci Adv. 2023 Jul 21;9(29):eadf4163. doi: 10.1126/sciadv.adf4163. Epub 2023 Jul 19.
Aging is a leading risk factor for cancer. While it is proposed that age-related accumulation of somatic mutations drives this relationship, it is likely not the full story. We show that aging and cancer share a common epigenetic replication signature, which we modeled using DNA methylation from extensively passaged immortalized human cells in vitro and tested on clinical tissues. This signature, termed CellDRIFT, increased with age across multiple tissues, distinguished tumor from normal tissue, was escalated in normal breast tissue from cancer patients, and was transiently reset upon reprogramming. In addition, within-person tissue differences were correlated with predicted lifetime tissue-specific stem cell divisions and tissue-specific cancer risk. Our findings suggest that age-related replication may drive epigenetic changes in cells and could push them toward a more tumorigenic state.
衰老 是癌症的一个主要危险因素。虽然有人提出，与年龄相关的体细胞突变积累驱动了这种关系，但这可能不是全部原因。我们表明，衰老和癌症具有共同的表观遗传复制特征，我们使用体外广泛传代的永生化人类细胞中的 DNA 甲基化来建模，并在临床组织上进行了测试。这个特征称为 CellDRIFT，它在多个组织中随年龄增长而增加，能够区分肿瘤和正常组织，在癌症患者的正常乳腺组织中升高，并在重编程时短暂重置。此外，个体内组织差异与预测的终生组织特异性干细胞分裂和组织特异性癌症风险相关。我们的研究结果表明，与年龄相关的复制可能会导致细胞中的表观遗传变化，并可能使它们向更具肿瘤发生能力的状态发展。
