Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK.
Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
Oncogene. 2023 Sep;42(37):2713-2724. doi: 10.1038/s41388-023-02802-7. Epub 2023 Aug 12.
Advances in sequencing have revealed a highly variegated landscape of mutational signatures and somatic driver mutations in a range of normal tissues. Normal tissues accumulate mutations at varying rates ranging from 11 per cell per year in the liver, to 1879 per cell per year in the bladder. In addition, some normal tissues are also comprised of a large proportion of cells which possess driver mutations while appearing phenotypically normal, as in the oesophagus where a majority of cells harbour driver mutations. Individual tissue proliferation and mutation rate, unique mutagenic stimuli, and local tissue architecture contribute to this highly variegated landscape which confounds the functional characterization of driver mutations found in normal tissue. In particular, our understanding of the relationship between normal tissue somatic mutations and tumour initiation or future cancer risk remains poor. Here, we describe the mutational signatures and somatic driver mutations in solid and hollow viscus organs, highlighting unique characteristics in a tissue-specific manner, while simultaneously seeking to describe commonalities which can bring forward a basic unified theory on the role of these driver mutations in tumour initiation. We discuss novel findings which can be used to inform future research in this field.
测序技术的进步揭示了一系列正常组织中突变特征和体细胞驱动突变的高度多样化景观。正常组织的突变积累速度各不相同，肝脏中每个细胞每年积累 11 个突变，膀胱中每个细胞每年积累 1879 个突变。此外，一些正常组织还包含很大比例的细胞，这些细胞虽然表型正常，但却携带驱动突变，就像在食管中一样，大多数细胞都携带驱动突变。个体组织的增殖和突变率、独特的诱变刺激以及局部组织结构共同导致了这种高度多样化的景观，这使得正常组织中发现的驱动突变的功能特征变得复杂。特别是，我们对正常组织体细胞突变与肿瘤起始或未来癌症风险之间关系的理解仍然很差。在这里，我们描述了实体和空心内脏器官中的突变特征和体细胞驱动突变，以组织特异性的方式突出其独特特征，同时寻求描述共性，从而提出一个关于这些驱动突变在肿瘤起始中作用的基本统一理论。我们讨论了可以用于指导该领域未来研究的新发现。
