人类正常组织在组织学上在老化过程中积累了显著的突变负担。突变的范围和谱系在迅速增生的和无法再生的组织及干细胞和它们的分化后代中是可比的。其中一些突变提高了适应性，导致克隆体出现，有时可以代替整个组织表面积。与癌症相比，在组织学上正常组织中的体细胞突变主要是单核苷酸变异。然而，这些突变和阳性克隆选择的存在仍然是实体组织潜在癌变转化的糟糕指标。组织学上正常组织中的常见克隆扩张突变也不一定代表相应组织癌症的最常见早期突变，表明选择压力存在不同。初步证据表明，基质和免疫系统随着年龄共同进化，可能影响选择动力学。在本文中，我们将详细探讨组织学上正常和前癌变的人类体细胞组织的突变景观，并讨论可以决定其中阳性选择突变命运的细胞内和环境因素。精确地确定这些癌变转化的决定因素将有助于发展早期癌症干预和预防策略。

Histologically normal human tissues accumulate significant mutational burden with age. The extent and spectra of mutagenesis are comparable both in rapidly proliferating and post-mitotic tissues and in stem cells compared to their differentiated progeny. Some of these mutations provide increased fitness, giving rise to clones which, at times, can replace the entire surface area of tissues. Compared to cancer, somatic mutations in histologically normal tissues are primarily single nucleotide variations. Interestingly though, the presence of these mutations and positive clonal selection in isolation remains a poor indicator of potential future cancer transformation in solid tissues. Common clonally expanded mutations in histologically normal tissues also do not always represent the most frequent early mutations in cancers of corresponding tissues, indicating differences in selection pressures. Preliminary evidence implies that stroma and immune system co-evolve with age, which may impact selection dynamics. In this review, we will explore the mutational landscape of histologically normal and pre-malignant human somatic tissues in detail and discuss cell-intrinsic and environmental factors that can determine the fate of positively selected mutations within them. Precisely pinpointing these determinants of cancer transformation would aid development of early cancer interventional and prevention strategies.