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Tobacco smoking and somatic mutations in human bronchial epithelium.

吸烟与人支气管上皮体细胞突变。

  • 影响因子:15.21
  • DOI:10.1038/s41586-020-1961-1
  • 作者列表:"Yoshida K","Gowers KHC","Lee-Six H","Chandrasekharan DP","Coorens T","Maughan EF","Beal K","Menzies A","Millar FR","Anderson E","Clarke SE","Pennycuick A","Thakrar RM","Butler CR","Kakiuchi N","Hirano T","Hynds RE","Stratton MR","Martincorena I","Janes SM","Campbell PJ
  • 发表时间:2020-02-01
Abstract

:Tobacco smoking causes lung cancer1-3, a process that is driven by more than 60 carcinogens in cigarette smoke that directly damage and mutate DNA4,5. The profound effects of tobacco on the genome of lung cancer cells are well-documented6-10, but equivalent data for normal bronchial cells are lacking. Here we sequenced whole genomes of 632 colonies derived from single bronchial epithelial cells across 16 subjects. Tobacco smoking was the major influence on mutational burden, typically adding from 1,000 to 10,000 mutations per cell; massively increasing the variance both within and between subjects; and generating several distinct mutational signatures of substitutions and of insertions and deletions. A population of cells in individuals with a history of smoking had mutational burdens that were equivalent to those expected for people who had never smoked: these cells had less damage from tobacco-specific mutational processes, were fourfold more frequent in ex-smokers than current smokers and had considerably longer telomeres than their more-mutated counterparts. Driver mutations increased in frequency with age, affecting 4-14% of cells in middle-aged subjects who had never smoked. In current smokers, at least 25% of cells carried driver mutations and 0-6% of cells had two or even three drivers. Thus, tobacco smoking increases mutational burden, cell-to-cell heterogeneity and driver mutations, but quitting promotes replenishment of the bronchial epithelium from mitotically quiescent cells that have avoided tobacco mutagenesis.

摘要

: 吸烟会导致肺cancer1-3,这是一个由香烟烟雾中的 60 多种致癌物直接损害和突变DNA4,5 驱动的过程。烟草对肺癌细胞基因组的深远影响是well-documented6-10,但缺乏正常支气管细胞的等效数据。在这里,我们对来自 16 名受试者的单个支气管上皮细胞的 632 个菌落的全基因组进行了测序。吸烟是突变负担的主要影响因素,通常每个细胞增加 1,000 到 10,000 个突变; 在受试者内部和受试者之间都大幅增加了变异; 并产生几个不同的突变标记的取代和插入和缺失。有吸烟史的个体中的一群细胞具有突变负担,与从未吸烟的人预期的突变负担相当: 这些细胞对烟草特异性突变过程的损伤较小,在戒烟者中比现在的吸烟者高四倍,并且端粒比突变较大的吸烟者长得多。驱动突变的频率随着年龄的增长而增加,影响了从未吸烟的中年受试者中 4-14% 的细胞。在当前吸烟者中,至少 25% 的细胞携带驱动突变,0-6% 的细胞具有两个甚至三个驱动。因此,吸烟增加了突变负担、细胞间异质性和驱动突变,但是戒烟促进了从避免烟草诱变的有丝分裂静止细胞补充支气管上皮。

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