德国马克斯·普朗克感染生物学研究所Thomas F. Meyer团队最近取得新进展。他们提出大肠菌素 DNA损伤特征表明对结直肠癌的突变影响。这一研究成果于2020年6月1日发表在《自然-医学》杂志上。

他们研究了大肠菌素（一种与某些大肠杆菌菌株相关的有效基因毒素）是否在受感染的人类结直肠细胞中造成了特定的DNA损伤特征。值得注意的是，大肠菌素诱导的DNA双链断裂的基因组，富含AT的六聚体序列基序，并具有独特的DNA形状特征。在数千个癌症基因组的大肠菌素靶位点进行的体细胞突变研究表明，该基序在结直肠癌中显著富集。

此外，确切的双链断裂位点对应于癌症基因组中的突变热点，让人想起以前在健康的结肠直肠上皮细胞中鉴定出的三核苷酸标记。本研究为大肠菌素在人类癌症中的病因学作用提供了证据。

研究人员表示，粘膜上皮是慢性细菌感染和伴随的毒素损伤的常见靶标，大多数癌症都起源于这种组织。

附：英文原文

Title: Colibactin DNA-damage signature indicates mutational impact in colorectal cancer

Author: Paulina J. Dziubaska-Kusibab, Hilmar Berger, Federica Battistini, Britta A. M. Bouwman, Amina Iftekhar, Riku Katainen, Tatiana Cajuso, Nicola Crosetto, Modesto Orozco, Lauri A. Aaltonen, Thomas F. Meyer

Issue&Volume: 2020-06-01

Abstract: 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.

DOI: 10.1038/s41591-020-0908-2

Source: https://www.nature.com/articles/s41591-020-0908-2