研究揭示人膀胱體細胞突變和選擇的廣泛異質性

研究揭示人膀胱體細胞突變和選擇的廣泛異質性

作者：

小柯機器人

發布時間：2020/10/3 23:00:10

英國惠康-桑格研究所Iigo Martincorena團隊的一項最新研究，揭示了人膀胱體細胞突變和選擇的廣泛異質性。該項研究成果發表在2020年10月2日出版的《科學》上。

研究人員利用靶向（n = 1914活檢）外顯子組（n = 655）和全基因組（n = 88）測序對來自20名個體的2097例膀胱活檢進行了測序。研究人員在17個基因中發現了廣泛的正向選擇。染色質重塑基因經常被突變，而在幾個主要的膀胱癌基因中卻沒有突變。選擇性存在廣泛的個體差異，不同的驅動基因主導著個體間的克隆情況。突變特徵在克隆和個體之間是異質的，這表明個體對誘變劑的暴露程度不同。

在22％的活檢組織中發現了APOBEC誘變的證據。對來自五名膀胱癌患者的多個活檢樣品進行測序使得其可以與無癌個體和不同組織學特徵進行比較。這項研究揭示了正常尿路上皮中突變過程和選擇的富集情況，並揭示克隆和個體之間存在很大的異質性。

研究人員表示，人膀胱中體細胞突變和克隆選擇的程度仍然未知。

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

Science：《科學》，創刊於1880年。隸屬於美國科學促進會，最新IF：41.037