From genotoxicity to oncogenicity: Uncovering the molecular signature of Helicobacter pylori in gastric cancer

Gastric Cancer (GC) is the third most common cause of cancer-related deaths. A major GC risk factors is an early infection with Helicobacter pylori (H.pylori). Growing body of evidence portrays a deleterious effect of H.pylori on genome integrity of the host. While this may imply a link between H.pylori genotoxicity and its oncogenicity, the biological mechanism/s of H.pylori-induced DNA damage and their role in GC tumorigenesis remain largely elusive.
By conducting genome-wide mapping of DNA damage in gastric cells upon H.pylori infection, we show that H.pylori infection results in thousands of recurrent double-stranded breaks (DSBs) across the genome. The structure and localization pattern of these breaks reflected DNA replication stalling. Such harmful event takes place in conditions of replication stress such as nucleotide depletion. Indeed, quantification of the dNTPs concentration in cells revealed dramatic reduction upon H.pylori infection. Consistent with that, H.pylori infection results in downregulation of the Ribonucleotide Reductase , the enzyme that responsible for dNTP synthesis. Strikingly, external supplementation of dNTPs strongly attenuated H.pylori-mediated damage. Finally, DSBs identified upon H.pylori infection show a significant co-localization with the breakpoints of structural variants (SVs) from gastric cancer patients. Together, our data imply that H.pylori genotoxicity, as well as its oncogenic potential, are rooted in its capacity to impose dNTP depletion in the host cell, which in turn results in replication fork collapse and DNA damage.