Cancer, Ageing and Somatic Mutation Programme, Wellcome Sanger Institute, Hinxton CB10 1SA, UK.
Department of Hematology, Erasmus University Medical Center, Rotterdam 3015 GD, Netherlands.
Science. 2020 Oct 2;370(6512):75-82. doi: 10.1126/science.aba8347.
The extent of somatic mutation and clonal selection in the human bladder remains unknown. We sequenced 2097 bladder microbiopsies from 20 individuals using targeted ( = 1914 microbiopsies), whole-exome ( = 655), and whole-genome ( = 88) sequencing. We found widespread positive selection in 17 genes. Chromatin remodeling genes were frequently mutated, whereas mutations were absent in several major bladder cancer genes. There was extensive interindividual variation in selection, with different driver genes dominating the clonal landscape across individuals. Mutational signatures were heterogeneous across clones and individuals, which suggests differential exposure to mutagens in the urine. Evidence of APOBEC mutagenesis was found in 22% of the microbiopsies. Sequencing multiple microbiopsies from five patients with bladder cancer enabled comparisons with cancer-free individuals and across histological features. This study reveals a rich landscape of mutational processes and selection in normal urothelium with large heterogeneity across clones and individuals.
人类膀胱中的体细胞突变和克隆选择的程度尚不清楚。我们使用靶向测序（= 1914 个微生物活检）、全外显子组测序（= 655 个）和全基因组测序（= 88 个）对 20 名个体的 2097 个膀胱微生物活检进行了测序。我们在 17 个基因中发现了广泛的阳性选择。染色质重塑基因经常发生突变，而几个主要的膀胱癌基因中则没有突变。选择在个体间存在广泛的差异，不同的驱动基因在个体间的克隆景观中占主导地位。突变特征在克隆和个体之间存在异质性，这表明尿液中存在不同的诱变剂暴露。在 22%的微生物活检中发现了 APOBEC 诱变的证据。对 5 名膀胱癌患者的 5 个微生物活检进行测序，使我们能够与无癌症个体和不同组织学特征进行比较。这项研究揭示了正常尿路上皮中丰富的突变过程和选择景观，克隆和个体之间存在很大的异质性。
