Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA.
Science. 2019 Jun 7;364(6444). doi: 10.1126/science.aaw0726.
How somatic mutations accumulate in normal cells is poorly understood. A comprehensive analysis of RNA sequencing data from ~6700 samples across 29 normal tissues revealed multiple somatic variants, demonstrating that macroscopic clones can be found in many normal tissues. We found that sun-exposed skin, esophagus, and lung have a higher mutation burden than other tested tissues, which suggests that environmental factors can promote somatic mosaicism. Mutation burden was associated with both age and tissue-specific cell proliferation rate, highlighting that mutations accumulate over both time and number of cell divisions. Finally, normal tissues were found to harbor mutations in known cancer genes and hotspots. This study provides a broad view of macroscopic clonal expansion in human tissues, thus serving as a foundation for associating clonal expansion with environmental factors, aging, and risk of disease.
体细胞突变在正常细胞中是如何积累的，目前还了解甚少。对来自 29 种正常组织的约 6700 个样本的 RNA 测序数据进行综合分析，揭示了多种体细胞变异，表明在许多正常组织中都可以发现宏观克隆。我们发现，暴露在阳光下的皮肤、食管和肺的突变负担高于其他测试组织，这表明环境因素可以促进体细胞镶嵌现象。突变负担与年龄和组织特异性细胞增殖率都有关，这突出表明突变是随着时间的推移和细胞分裂次数的增加而积累的。最后，在已知的癌症基因和热点中发现了正常组织的突变。这项研究为人类组织中的宏观克隆扩张提供了广泛的视角，从而为将克隆扩张与环境因素、衰老和疾病风险联系起来奠定了基础。
