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

Various species of the intestinal microbiota have been associated with the
development of colorectal cancer (CRC), 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 colibactin. This compound alkylates DNA on adenine residues and
induces double strand breaks in cultured cells. Here, we exposed human intestinal
organoids to genotoxic pks+ Escherichia coli by repeated luminal injection over a
period of 5 months. Whole genome sequencing (WGS) 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 3668 human metastatic cancer genomes,
predominantly in a subset of CRC cases. 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.EGA study EGAS00001003934

多种肠道菌群物种与结直肠癌（colorectal cancer, CRC）的发生发展密切相关，但细菌在致癌突变发生中的直接作用尚未得到证实。大肠杆菌（Escherichia coli）可携带致病性岛pks，该基因岛编码一组合成大肠杆菌素（colibactin）的酶。该化合物可对腺嘌呤残基上的DNA进行烷基化修饰，并在培养细胞中诱导双链断裂。本研究通过为期5个月的反复腔道注射，将携带pks的致基因毒性大肠杆菌暴露于人肠道类器官。对暴露前后的克隆类器官开展全基因组测序（whole genome sequencing, WGS），结果显示其存在独特的突变特征，而注射同基因pks突变株细菌的类器官则无该突变特征。同样的突变特征在3668份人类转移性癌症基因组的亚组中被检测到，且主要富集于部分结直肠癌病例中。本研究阐明了结直肠癌中一种独特的突变特征，并暗示其背后的突变过程直接源于既往暴露于携带产大肠杆菌素pks致病性岛的细菌。EGA研究编号：EGAS00001003934