英国惠康-桑格研究所Iigo Martincorena团队的一项最新研究，揭示了人膀胱体细胞突变和选择的广泛异质性。该项研究成果发表在2020年10月2日出版的《科学》上。

研究人员利用靶向（n = 1914活检）外显子组（n = 655）和全基因组（n = 88）测序对来自20名个体的2097例膀胱活检进行了测序。研究人员在17个基因中发现了广泛的正向选择。染色质重塑基因经常被突变，而在几个主要的膀胱癌基因中却没有突变。选择性存在广泛的个体差异，不同的驱动基因主导着个体间的克隆情况。突变特征在克隆和个体之间是异质的，这表明个体对诱变剂的暴露程度不同。

在22％的活检组织中发现了APOBEC诱变的证据。对来自五名膀胱癌患者的多个活检样品进行测序使得其可以与无癌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突变过程和选择的富集情况，并揭示克隆和个体之间存在很大的异质性。

研究人员表示，人膀胱中体细胞突变和克隆选择的程度仍然未知。

附：英文原文

Title: Extensive heterogeneity in somatic mutation and selection in the human bladder

Author: Andrew R. J. Lawson, Federico Abascal, Tim H. H. Coorens, Yvette Hooks, Laura O’Neill, Calli Latimer, Keiran Raine, Mathijs A. Sanders, Anne Y. Warren, Krishnaa T. A. Mahbubani, Bethany Bareham, Timothy M. Butler, Luke M. R. Harvey, Alex Cagan, Andrew Menzies, Luiza Moore, Alexandra J. Colquhoun, William Turner, Benjamin Thomas, Vincent Gnanapragasam, Nicholas Williams, Doris M. Rassl, Harald Vhringer, Sonia Zumalave, Jyoti Nangalia, José M. C. Tubío, Moritz Gerstung, Kourosh Saeb-Parsy, Michael R. Stratton, Peter J. Campbell, Thomas J. Mitchell, Iigo Martincorena

Issue&Volume: 2020/10/02

Abstract: The extent of somatic mutation and clonal selection in the human bladder remains unknown. We sequenced 2097 bladder microbiopsies from 20 individuals using targeted (n = 1914 microbiopsies), whole-exome (n = 655), and whole-genome (n = 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.

DOI: 10.1126/science.aba8347

Source: https://science.sciencemag.org/content/370/6512/75