A predictive signature for oxaliplatin and 5-fluorouracil based chemotherapy in locally advanced gastric cancer

Qinchuan Wang, Xiyong Liu, Chen Chen, Jida Chen, Beisi Xu, Lini Chen, Jichun Zhou, Yasheng Huang, Wenjun Chen, Rongyue Teng, Wenhe Zhao, Lidan Jin, Jun Shen, Jianguo Shen, Yun Yen, Linbo Wang

研究成果: 雜誌貢獻文章同行評審

摘要

Adjuvant chemotherapy(AC) plays a substantial role in the treatment of locally advanced gastric cancer (LAGC), but the response remains poor. We aims to improve its efficacy in LAGC. Therefore, we identified the expression of eight genes closely associated with platinum and fluorouracil metabolism (RRM1, RRM2, RRM2B, POLH, DUT, TYMS, TYMP, MKI67) in the discovery cohort (N=291). And we further validated the findings in TCGA (N=279) and GEO. Overall survival (OS) was used as an endpoint. Univariate and multivariate Cox models were applied. A multivariate Cox regression model was simulated to predict the OS. In the discovery cohort, the univariate Cox model indicated that AC was beneficial to high-RRM1, high-DUT, low-RRM2, low-RRM2B, low-POLH, low-KI67, low-TYMS or low-TYMP patients, the results were validated in the TCGA cohort. The multivariate Cox model showed consistent results. Cumulative analysis indicated that patients with low C-Score respond poorly to the AC, whereas the high and medium C-Score patients significantly benefit from AC. A risk model based on the above variables successfully predicted the OS in both cohorts (AUC=0.75 and 0.67, respectively). Further validation in a panel of gastric cancer cell (GC) lines (N=37) indicated that C-Score is significantly associated with IC50 value to fluorouracil. Mutation profiling showed that C-Score was associated with the number and types of mutations. In conclusion, we successfully simulated a predictive signature for the efficacy of AC in LAGC patients and further explored the potential mechanisms. Our findings could promote precision medicine and improve the prognosis of LAGC patients.

原文英語
文章編號100901
期刊Translational Oncology
14
發行號1
DOIs
出版狀態已發佈 - 一月 2021

ASJC Scopus subject areas

  • 腫瘤科
  • 癌症研究

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