Abstract
_Helicobacter pylori_ (_H. pylori_), a bacteria which chronically infects the stomach of approximately half people in the world, is a risk factor for the development of gastric cancer (GC). However, the detailed mechanism by which _H. pylori_ infection induces GC development remains unclear. Intermittent injection of the _H. pylori_ CagA protein in to its host cell, inhibits the nuclear translocation of BRCA1/BRCA2-the DNA repair proteins involved prominently in breast cancer development. Interestingly, hereditary breast and ovarian cancer syndrome (HBOC) is associated with GC development. Here, we aimed to understand the molecular link between _H. pylori_ infection, _BRCA1/2_ pathogenic variants (PVs), GC and higher incidence of GC in HBOC families. To do so, in this retrospective clinical observation study, we checked the database of Japanese patients undergoing precision treatment using cancer genomic medicine. Indeed, we found a higher incidence of GC in HBOC families having germline pathogenic variants (GPVs) of _BRCA1/2_ (2.95 % vs. 0.78% (in non-HBOC families). Next we, found that 96.1 % _H. pylori_ infected patients received cancer genomic medicine examination for advanced GC, and > 16% advanced GC patients had _gBRCA2_ PVs. Moreover, histological examination of GC tumor tissue showed that gastric mucosa epithelial cells infected with CagA-positive _H. pylori_ strains were lacking in nuclear BRCA1. Further, we found that expressing wildtype BRCA1/2 in the _Gan_ mice (a mouse model of human GC), inhibited GC development. Thus, _gBRAC1/2_ PVs and _H. pylori_ infection synergistically increase the risk of GC development. Our study thus highlights the need for early eradication of _H. pylori _infection in HBOC family members to prevent GC development. Further, it indicates that that poly(ADP-ribose) polymerases (PARPs) inhibitors will be effective in halting development and progression of GCs in HBOC families with _gBRCA1/2_ PVs.