Hayashi Takuma, Sano Kenji, Okada Mako, Ura Takashi, Konishi Ikuo
Cancer Medicine, National Hospital Organization Kyoto Medical Center, Kyoto 612-8555, Japan.
Pathological Division, Shinshu University Hospital, Matsumoto, , Nagano 390-0877, Japan.
World J Oncol. 2024 Aug;15(4):722-730. doi: 10.14740/wjon1871. Epub 2024 Jul 5.
(), a bacterium which chronically infects the stomach of approximately half the world's population, is a risk factor for the development of gastric cancer (GC). However, the underlying mechanism whereby infection induces GC development remains unclear. Intermittent injection of the cytotoxin-associated gene A antigen (CagA) protein into its host cell inhibits nuclear translocation of BRCA1/BRCA2, DNA repair proteins involved in the development of breast cancer/ovarian cancer. Interestingly, hereditary breast and ovarian cancer (HBOC) syndrome is associated with GC development. Here, we aimed to clarify the molecular link between infection, pathogenic variants (PVs), GC and higher GC incidence in HBOC families.
We retrospectively reviewed data from Japanese patients undergoing precision treatment using cancer genomic medicine.
We found a higher GC incidence in HBOC families having germline pathogenic variants (GPVs) of (2.95% vs. 0.78% in non-HBOC families). Next, we found that 96.1% of -infected patients received cancer genomic medicine for advanced GC, and > 16% advanced GC patients had PVs. Furthermore, expressing wild-type BRCA1/2 in mice (a mouse model of human GC) inhibited GC development. Thus, PVs and infection synergistically increase the risk of GC development.
Our study highlights the need to investigate the potential of therapeutic agents against BRCA1/2 PVs to avoid the development of GC in HBOC families. In addition, our results suggest that poly (ADP-ribose) polymerase (PARP) inhibitors could potentially inhibit GC development and progression with gBRCA1/2 PVs.
幽门螺杆菌可长期感染全球约一半人口的胃部，是胃癌（GC）发生的一个风险因素。然而，幽门螺杆菌感染诱发胃癌发生的潜在机制仍不清楚。向宿主细胞间歇性注射细胞毒素相关基因A抗原（CagA）蛋白会抑制BRCA1/BRCA2的核转位，BRCA1/BRCA2是参与乳腺癌/卵巢癌发生的DNA修复蛋白。有趣的是，遗传性乳腺癌和卵巢癌（HBOC）综合征与胃癌发生有关。在此，我们旨在阐明幽门螺杆菌感染、致病变异（PVs）、胃癌以及HBOC家族中较高的胃癌发病率之间的分子联系。
我们回顾性分析了接受癌症基因组医学精准治疗的日本患者的数据。
我们发现携带幽门螺杆菌种系致病变异（GPVs）的HBOC家族中胃癌发病率更高（2.95%，而非HBOC家族为0.78%）。接下来，我们发现96.1%的幽门螺杆菌感染患者因晚期胃癌接受癌症基因组医学治疗，且>16%的晚期胃癌患者有幽门螺杆菌PVs。此外，在人胃癌小鼠模型中表达野生型BRCA1/2可抑制胃癌发生。因此，幽门螺杆菌PVs和幽门螺杆菌感染协同增加胃癌发生风险。
我们的研究强调有必要研究针对BRCA1/2 PVs的治疗药物在避免HBOC家族发生胃癌方面的潜力。此外，我们的结果表明聚（ADP - 核糖）聚合酶（PARP）抑制剂可能抑制携带种系BRCA1/2 PVs的胃癌发生和进展。
