The mucosal epithelium is a common target of damage by chronic bacterial infections and the accompanying toxins, and most cancers originate from this tissue. We investigated whether colibactin, a potent genotoxin¹ associated with certain strains of Escherichia coli², creates a specific DNA-damage signature in infected human colorectal cells. Notably, the genomic contexts of colibactin-induced DNA double-strand breaks were enriched for an AT-rich hexameric sequence motif, associated with distinct DNA-shape characteristics. A survey of somatic mutations at colibactin target sites of several thousand cancer genomes revealed notable enrichment of this motif in colorectal cancers. Moreover, the exact double-strand-break loci corresponded with mutational hot spots in cancer genomes, reminiscent of a trinucleotide signature previously identified in healthy colorectal epithelial cells³. The present study provides evidence for the etiological role of colibactin in human cancer.

黏膜上皮细胞是慢性细菌感染和伴随的毒素损伤的常见目标，大多数癌症起源于该组织。我们调查了colibactin，一种与某些大肠杆菌^{2菌株相关的强基因毒素1}，在受感染的人类结肠直肠细胞中产生特定的 DNA 损伤特征。值得注意的是，大肠杆菌素诱导的 DNA 双链断裂的基因组背景富含 AT 丰富的六聚体序列基序，与不同的 DNA 形状特征相关。对数千个癌症基因组的大肠杆菌素靶位点的体细胞突变的调查揭示了该基序在结直肠癌中的显着富集。此外，确切的双链断裂基因座与癌症基因组中的突变热点相对应，这让人想起以前在健康结直肠上皮细胞中发现的三核苷酸特征³。本研究为大肠杆菌素在人类癌症中的病因学作用提供了证据。