Drug Repositioning Study For Hepatocellular Carcinoma Based On Tissue-specific Pathway And Gene Mutation

Hepatocellular carcinoma(HCC)is a significant health problem worldwide and annual number of cases are nearly more than 700,000.During the treatment of HCC,it tends to have drug resistance problems,resulting in effective treatment of drugs continue to decrease,in the end there will be no drug available.The development of a new drug is very costly and time-consuming,and it is also accompanied by a higher risk.Drug repositioning can explore the potential efficacy of the old drugs,these potential effects can cure the disease which is not within the scope of its efficacy.Drug repositioning reduces the time and cost.The existing drug repositioning methods only consider statistical differences,but discard many important biological information.In this paper,we propose two new ways to solve this problem from different aspects.In the first method,we propose a new drug repositioning approach to predict the association between drugs and HCC based on KEGG functional pathways and tissue specific network.Firstly,we map genes related to HCC to the liver-specific protein interaction network and get an extended tissue-specific gene set of HCC.Then,based on the extended gene set of HCC,we extract 12 enriched KEGG pathways.Finally,using Kolmogorov–Smirnov statistic,we calculate the therapeutic scores of drugs based on the 12 tissue-specific pathways.Furthermore,we validate the top-six potentially related drugs for HCC by Comparative Toxicogenomics Database(CTD)and Pub Med literatures,and CMap profiles similarity analysis and KEGG enrichment analysis.In the second method,we propose a method based on the combination of gene mutation data and gene differential expression data.Firstly,we screen the collection of hepatocellular feature genes that frequently mutated in most samples of HCC based on somatic mutation data.Then,the gene expression data of HCC from TCGA are combined to classify the gene set of HCC.Finally,Finally,using Kolmogorov–Smirnov statistic,we calculate the therapeutic scores of drugs.We find five drugs that may be associated with HCC.In this part of the experimental validations,we take the same analysis strategy as the second chapter.In summary,this article not only provides an effective strategy for screening diseasecharacteristics,but also provides a new methodological framework for drug repositioning research,thus providing new therapeutic drugs for the treatment of liver cancer.