Exploring effects of DNA methylation and gene expression on pan-cancer drug response by mathematical models

被引:1
作者
Lv, Wenhua [1 ]
Zhang, Xingda [2 ]
Dong, Huili [3 ]
Wu, Qiong [3 ]
Sun, Baoqing [4 ]
Zhang, Yan [4 ]
机构
[1] Harbin Med Univ, Coll Bioinformat Sci & Technol, Harbin 150086, Peoples R China
[2] Harbin Med Univ Canc Hosp, Dept Breast Surg, Harbin 150081, Heilongjiang, Peoples R China
[3] Harbin Inst Technol, Sch Life Sci & Technol, Computat Biol Res Ctr, Harbin 150001, Peoples R China
[4] Guangzhou Med Univ, Guangzhou Inst Resp Hlth, State Key Lab Resp Dis, Guangzhou 51000, Peoples R China
基金
中国国家自然科学基金;
关键词
Drug response; DNA methylation; epigenetics; gene expression; prediction models; pan-cancer; EPIGENETICS; INHIBITOR; MARKER; EPIGENOMICS; LANDSCAPE; GROWTH; HSP90; GRB7;
D O I
10.1177/15353702211007766
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
Since genetic alteration only accounts for 20%-30% in the drug effect-related factors, the role of epigenetic regulation mechanisms in drug response is gradually being valued. However, how epigenetic changes and abnormal gene expression affect the chemotherapy response remains unclear. Therefore, we constructed a variety of mathematical models based on the integrated DNA methylation, gene expression, and anticancer drug response data of cancer cell lines from pan-cancer levels to identify genes whose DNA methylation is associated with drug response and then to assess the impact of epigenetic regulation of gene expression on the sensitivity of anticancer drugs. The innovation of the mathematical models lies in: Linear regression model is followed by logistic regression model, which greatly shortens the calculation time and ensures the reliability of results by considering the covariates. Second, reconstruction of prediction models based on multiple dataset partition methods not only evaluates the model stability but also optimizes the drug-gene pairs. For 368,520 drug-gene pairs with P < 0.05 in linear models, 999 candidate pairs with both AUC >= 0.8 and P < 0.05 were obtained by logistic regression models between drug response and DNA methylation. Then 931 drug-gene pairs with 45 drugs and 491 genes were optimized by model stability assessment. Integrating both DNA methylation and gene expression markedly increased predictive power for 732 drug-gene pairs where 598 drug-gene pairs including 44 drugs and 359 genes were prioritized. Several drug target genes were enriched in the modules of the drug-gene-weighted interaction network. Besides, for cancer driver genes such as EGFR, MET, and TET2, synergistic effects of DNA methylation and gene expression can predict certain anticancer drugs' responses. In summary, we identified potential drug sensitivity-related markers from pan-cancer levels and concluded that synergistic regulation of DNA methylation and gene expression affect anticancer drug response.
引用
收藏
页码:1626 / 1642
页数:17
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