Nature:基因毒性大肠杆菌导致大肠癌的新证据
  • 携带pks毒力基因岛的大肠杆菌可产生基因毒素colibactin;
  • 将人肠道类器官与大肠杆菌进行长期共培养(5个月),用全基因组测序分析类器官发生的基因突变;
  • 与不产colibactin的大肠杆菌相比,pks+大肠杆菌主要使类器官发生两类特征性DNA突变(独特的单碱基替换和插入缺失特征);
  • 这些突变特征在一部分人类癌症样本(以结直肠癌为主)中也存在,包括一些致癌突变,提示这些突变可能是源于与产colibactin的pks+细菌的长期接触。
主编推荐语
mildbreeze
Colibactin存在于携带pks毒力基因岛的大肠杆菌中,是近两年来研究得比较多的促大肠癌细菌产物。研究显示,Colibactin具有基因毒性,可导致DNA双链断裂,从而引起宿主细胞基因突变,但由其造成的基因突变究竟具有哪些特征尚不清楚。Nature上周上线的一项最新研究,以人类肠道类器官作为研究模型,首次从基因突变特征的角度为这类大肠杆菌与大肠癌之间的因果性关联,提供了直接的支持性证据,为防治大肠癌提供了新的参考信息。值得注意的是,传统益生菌大肠杆菌Nissle 1917中也存在pks毒力基因岛,而且有研究显示该菌的某些益生作用与pks存在关联,提示该益生菌的长期安全性还需要进一步研究。
关键字
延伸阅读本研究的原文信息和链接出处,以及相关解读和评论文章。欢迎读者朋友们推荐!
图片
Nature [IF:42.778]

Mutational signature in colorectal cancer caused by genotoxic pks+ E. coli

基因毒性pks+大肠杆菌导致的结直肠癌的突变特征

10.1038/s41586-020-2080-8

2020-02-27, Article

Abstract & Authors:展开

Abstract:收起
Various species of the intestinal microbiota have been associated with the development of colorectal cancer (CRC)1,2, yet a direct role of bacteria in the occurrence of oncogenic mutations has not been established. Escherichia coli can carry the pathogenicity island pks, which encodes a set of enzymes that synthesize colibactin3. This compound is believed to alkylate DNA on adenine residues4,5 and induces double-strand breaks in cultured cells3. Here, we expose human intestinal organoids to genotoxic pks+ E. coli by repeated luminal injection over a period of 5 months. Whole-genome sequencing of clonal organoids before and after this exposure reveals a distinct mutational signature, absent from organoids injected with isogenic pks-mutant bacteria. The same mutational signature is detected in a subset of 5,876 human cancer genomes from two independent cohorts, predominantly in CRC. Our study describes a distinct mutational signature in CRC and implies that the underlying mutational process directly results from past exposure to bacteria carrying the colibactin-producing pks pathogenicity island.

First Authors:
Cayetano Pleguezuelos-Manzano,Jens Puschhof,Axel Rosendahl Huber

Correspondence Authors:
Ruben van Boxtel,Hans Clevers

All Authors:
Cayetano Pleguezuelos-Manzano,Jens Puschhof,Axel Rosendahl Huber,Arne van Hoeck,Henry M Wood,Jason Nomburg,Carino Gurjao,Freek Manders,Guillaume Dalmasso,Paul B Stege,Fernanda L Paganelli,Maarten H Geurts,Joep Beumer,Tomohiro Mizutani,Reinier van der Linden,Stefan van Elst,Genomics England Research Consortium,Janetta Top,Rob J L Willems,Marios Giannakis,Richard Bonnet,Phil Quirke,Matthew Meyerson,Edwin Cuppen,Ruben van Boxtel,Hans Clevers

图片
BBC News新闻网站

E. coli gut infection linked to bowel cancer

2020-02-27

图片
ScienceDaily新闻网站

A common gut microbe secretes a carcinogen

2020-02-27

图片
Nature Reviews Gastroenterology and Hepatology期刊

Microbiota and colorectal cancer: colibactin makes its mark

2020-04-21

图片
人体微生物组与健康微信公众号

Nature:遗传印迹揭示导致癌症发生的肠道微生物

2020-02-28

评论