Identification of bacterial DNA integration into the human cancer genome

Abstract

Cancer is a disease characterized by uncontrolled cell proliferation. The primary factor promoting the transformation of normal cells into cancerous cells is the accumulation of somatic mutations. One example of these mutations that promotes carcinogenesis is the integration of DNA into the human genome. In 2002, ~90% of cervical cancer genomes had human papillomavirus DNA integrations and resulted in ~275,000 deaths. While viral DNA integrations are a known mutagen, the integration of bacterial DNA into the somatic human genome has not been described. Considering that there are 10x more bacterial cells than human cells in the human body, there is ample opportunity for integration of bacterial DNA into the somatic human genome. Using public next-generation sequencing data from The Cancer Genome Atlas, nine cancer types were analyzed for evidence of bacterial DNA integrations. In acute myeloid leukemia samples hundreds of thousands of reads support the integration of Acinetobacter-like DNA into the human mitochondrial genome. In addition, data from multiple samples of stomach adenocarcinomas support the integration of Pseudomonas-like DNA into the promoter of four human genes. To further characterize the bacterial DNA integrations (BDI), the most statistically likely configuration of the bacterial and human DNA fragments was calculated. The models demonstrated that the DNA fragments supporting the bacterial DNA integrations are rich in guanine nucleotides. Furthermore, these models demonstrate the integrated fragments of bacterial DNA have complex transcript secondary structure in the native bacterial transcripts. Lastly, a luciferase reporter assay shows that a bacterial DNA integration significantly decreases the activity of a human promoter in an orientation-specific manner. These data support that the BDI may disrupt the activity of the human promoter by altering the secondary structure of the transcript. Together, these data support the hypothesis that bacterial DNA integrates into the somatic human genome. Given that the BDI re-created here alters the regulation of human genes, BDIs have the potential to be deleterious mutations. Future work should focus on determining if BDIs play a role in promoting carcinogenesis.