TY - JOUR
T1 - A predictive signature for oxaliplatin and 5-fluorouracil based chemotherapy in locally advanced gastric cancer
AU - Wang, Qinchuan
AU - Liu, Xiyong
AU - Chen, Chen
AU - Chen, Jida
AU - Xu, Beisi
AU - Chen, Lini
AU - Zhou, Jichun
AU - Huang, Yasheng
AU - Chen, Wenjun
AU - Teng, Rongyue
AU - Zhao, Wenhe
AU - Jin, Lidan
AU - Shen, Jun
AU - Shen, Jianguo
AU - Yen, Yun
AU - Wang, Linbo
N1 - Funding Information:
This work was supported by National Natural Science Foundation of China (No. 81972453 , No. 81972597 , No. 81602471 and No. 81672729 ), Natural Science Foundation of Zhejiang ( Q16H160010 , LY18H160005 ), Zhejiang Medical Scientific Research Foundation ( 2020RC022 ).
Publisher Copyright:
© 2020 The Authors
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2021/1
Y1 - 2021/1
N2 - 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.
AB - 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.
KW - Adjuvant chemotherapy
KW - Locally advanced gastric cancer
KW - Mutation
KW - Overall survival
KW - Prediction
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U2 - 10.1016/j.tranon.2020.100901
DO - 10.1016/j.tranon.2020.100901
M3 - Article
AN - SCOPUS:85092759171
SN - 1936-5233
VL - 14
JO - Translational Oncology
JF - Translational Oncology
IS - 1
M1 - 100901
ER -