Genetic Variation Analysis Of Antineoplastic Drug-related Genes Based On Large Scale Population Sequencing Data

Background: Cancer has become the second leading cause of death in the world,with the number of new cancer cases and cancer deaths in China ranking first in the world.In 2020,there were 19.29 million cancer patients in the world,of which China accounted for 23.7%,or about 4.57 million cases.China has become a disaster area for cancer.Drug therapy is the most common way to control the development of cancer,but the effectiveness of drugs is not high,and the effectiveness of antineoplastic drugs is only about 25%.Polymorphisms in genes encoding drug metabolism enzymes,drug transporters,drug receptors can alter drug efficacy or the risk of adverse reactions in patients.In addition,there are great genetic differences between different regions or different races.As China is a country with a large population,it is necessary to identify the genetic characteristics of genes related to antineoplastic drugs used by Chinese people in the process of implementing precision medicine for cancer.Purpose: Based on the genome-wide analysis of large-scale population sequencing data,calculate the population mutation frequency,systematically analyze the basic situation and population differences of the genetic variation of antitumor drug-related genes,and construct a gene detection panel for individualized tumor medicine.Methods: The list of anti-tumor drugs was determined based on the drug information published by FDA and CFDA,and drug-related genes were determined through databases or clinical guidelines such as Drug Bank,Pharm GKB,FDA biomarker and CPIC.The population mutation frequency of a single locus was estimated based on the maximum likelihood method,and the calculation process was completed on the Alibaba Cloud platform.Use GATK,ANNOVAR,PROVEAN,SIFT and other software to perform quality control,annotation and functional prediction of mutations,and use Perl,Python,R and other computer languages to perform statistical analysis on mutation results.The QTL information comes from the QTLBase database.Drawing tools used include Graph Pad,Cytoscape,and TBtools.The R packages used are maps,ggcorrplot,ggplot2.Results: Data collection and processing: We collected a total of206,604 NIPT samples from mainland China for genome-wide analysis,and identified 104 antitumor drugs and 517 drug-related genes;in addition,we also established a set of genes suitable for this study.The data processing pipeline and maximum likelihood method were used to estimate the population mutation frequency.Overview of genetic variation in antitumor drug-related genes: We found a total of 201,774 genetic variants in antitumor drug-related genes,consisting of 41,955 new mutations and159,819 known mutations.About 90% of the new mutations are rare mutations,and the frequency Less than 1%;whether it is a new mutation or a known mutation,the most common type is intron mutation,followed by UTR mutation and exon mutation;genetic variation analysis of important genes shows that many genetic mutations are included in clinical guidelines.The frequency of variants in the Chinese population is not high,such as DPYD*2A,TPMT*3,and the intermediate metabolizers and slow metabolizers of important metabolic enzymes account for a large proportion in the population,such as UGT1A1,CYP2D6,NUDT15,etc.;The results of intra-species and inter-ethnic differences analysis of the genetic variation of anti-tumor drug-related genes showed that there were no intra-species differences in the Chinese population,but there were obvious racial differences.Preliminary construction of anti-tumor drug gene detection panel: mutation deleterious prediction and QTL analysis results show that 12 predicted deleterious mutations and 8 important QTL sites may affect the efficacy and safety of 5’-FU drugs.Conclusion: A processing flow of 200,000 NIPT data was established,and based on the published research combined with the data characteristics of this study,the population mutation frequency was calculated using the maximum likelihood method;the overview of genetic variation of antitumor drug-related genes revealed the Chinese population It has distinct genetic characteristics that are different from other ethnic groups,and the mutation status of important genes and variants in the Chinese population and the proportion of metabolotypes in the population;mutation toxicity prediction and QTL analysis revealed that it may affect the use of5’-FU drugs The key sites,these sites initially complement the gene detection panel of 5’-FU drugs.