Hit-and-Run gastric carcinogenesis caused by H. pylori-mediated BRCA1 inactivation

2023 Fiscal Year Final Research Report

• Project/Area Number: 21H04804
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Medium-sized Section 50:Oncology and related fields
• Research Institution: Microbial Chemistry Research Foundation (2022-2023); The University of Tokyo (2021)
• Principal Investigator: Hatakeyama Masanori 公益財団法人微生物化学研究会, 微生物化学研究所, 部長 (40189551)
• Project Period (FY): 2021-04-05 – 2024-03-31
• Keywords: 胃がん / ピロリ菌 CagA / BRCA1 / BRCAness / 相同組換え / DNA複製フォーク / ゲノム不安定性

Outline of Final Research Achievements

The Helicobacter pylori CagA oncoprotein plays a vital role in the development of gastric cancer. Upon delivery into gastric epithelial cells via the bacterial micro-syringe, termed the type IV secretion system, CagA physically interacts with the serine/threonine kinase PAR1b and inactivates kinase activity. This study found that PAR1b promotes cytoplasmic-to-nuclear translocalization of the breast and ovarian cancer susceptibility gene product BRCA1 via phosphorylation on Ser-616. Upon injection into the host cells, however, CagA inhibits the nuclear delivery of cytoplasmic BRCA1 by turning off PAR1b-mediated BRCA1 phosphorylation, thereby depleting nuclear BRCA1, which elicits genomic instability similar to that induced by BRCA1 gene mutation. The risk of developing gastric cancer in individuals carrying a pathogenic BRCA1 variant (such as BRCA1, BRCA2, or PALB2) is robustly increased in the presence of H. pylori infection.

Free Research Field

感染腫瘍学・分子腫瘍学

Academic Significance and Societal Importance of the Research Achievements

本研究から、ピロリ菌感染を基盤とする胃がんの発症と遺伝性乳がん・卵巣がん (HBOC) 発症との間に共通の分子機構が働いているというこれまで全く予想されてこなかった結論が導かれた、BRCA1に代表されるDNA相同組換え遺伝子の病的バリアント保有者は数百人に一人の頻度で存在する。これら病的バリアントの保有のみでは胃発がんリスクは微増にとどまるが、病的バリアント保有者がピロリ菌感染を受けている場合、胃発がんリスクは飛躍的に増加する。ピロリ菌感染者におけるBRCA関連遺伝子病的バリアントのスクリーニングは、胃がん高リスク群絞り込みの重要な手段になると考えられる。