研究揭示CRC中pks+大肠杆菌突变特征
2020-03-06   阅读:603   来源:自然

荷兰马克西玛公主小儿肿瘤学中心Hans CleversRuben van Boxtel研究组揭示遗传毒性pks +大肠杆菌在大肠癌(CRC)中的突变特征。这一研究成果发表在2020227日出版的《自然》杂志上。

他们通过在5个月的时间内反复进行腔内注射,将人类肠道类器官接触具有遗传毒性的pks +大肠杆菌。接触前后的克隆类器官的全基因组测序揭示了独特的突变特征,而注射等位基因pks突变细菌的类器官没有这种特征。在两个独立研究中的5876个人类癌症基因组亚群集中检测到相同的突变特征,主要在CRC中。他们的研究描述了CRC中独特的突变特征,并表明潜在的突变过程直接来自于过去接触携带产生大肠杆菌素pks致病岛的细菌。

研究人员表示,肠道菌群的各种物种与CRC进展有关,但尚未确定细菌在致癌突变中的直接作用。大肠杆菌可以携带致病岛pks,该pks编码一组合成黏菌素的酶。据悉该化合物可将腺嘌呤残基上的DNA烷基化,并在培养细胞中诱导双链断裂。

附:英文原文

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

Author: 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, Janetta Top, Rob J. L. Willems, Marios Giannakis, Richard Bonnet, Phil Quirke, Matthew Meyerson, Edwin Cuppen, Ruben van Boxtel, Hans Clevers

Issue&Volume: 2020-02-27

Abstract: 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.

DOI: 10.1038/s41586-020-2080-8

编辑:小柯机器人

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