DNA damage repair and survival outcomes in advanced gastric cancer patients treated with first‐line chemotherapy

摘要: The DNA damage response (DDR) network is exploited by cancer cells to withstand chemotherapy. Gastric (GC) carries deregulation of the DDR and harbors genetic defects that fuel its activation. ATM-Chk2 ATR-Chk1-Wee1 axes are deputed initiate repair. Overactivation these pathways in may represent an adaptive for compensating deregulating G1 -S transition (e.g., TP53) ATM/ATR-initiated repair ARID1A). We hypothesized DDR-linked biomarkers predict clinical outcomes GC patients treated with Immunohistochemical assessment kinases (pATM, pChk2, pChk1 pWee1) markers (γ-H2AX pRPA32) was performed biological samples from 110 advanced first-line chemotherapy, either phase II trials or routine practice. In 90 patients, this characterization integrated targeted ultra-deep sequencing evaluating mutational status TP53 ARID1A. recorded a positive association between investigated biomarkers. combination two (γ-H2AXhigh /pATMhigh ) adverse factor both progression-free survival (multivariate Cox: HR 2.23, 95%CI: 1.47-3.40) overall HR: 2.07, 1.20-3.58). relationship γ-H2AXhigh model consistent across different backgrounds maintained ARID1A wild-type setting. Conversely, no longer observed ARID1A-mutated subgroup. negatively impacted ARID1A, but apparently not mutations, affects predictive significance.