Pharmacogenomics Study Of Treatment Response To Platinum-pemetrexed In Non-small Cell Lung Cancer

Objective:In the clinical treatment of tumors,different patients with the same tumor will respond differently to the same drug and dose.The genetic background is an important factor affecting the patient's drug sensitivity and therapeutic response.Screening patients at the genetic level before treatment and individualizing treatment based on the patient's genotype are of great significance for improving drug response.In this study,pharmacogenomics research was used to find SNPs associated with the response to platinum-pemetrexed in the treatment of non-small cell lung cancer(NSCLC),and provide experimental evidence for individualized treatment of tumors.Methods:A total of 47 pre-treatment blood samples from NSCLC patients were collected and their clinical information was summarized.All enrolled patients received platinum-pemetrexed.The sample DNA was extracted and the whole genome polymorphism of samples which met the quality control was detected by PMRA chip.Using response as a phenotype,we performed genome-wide association study(GWAS)on genotype and phenotype by gPLINK software.Functional prediction and expression quantitative trait loci(eQTL)were performed on significant SNPs using RegulomeDB,UCSC genome browser,PolymiRTS and GTEx.GEO expression profile data(GSE15709)was used to explore the association between RGS5 gene expression and platinum sensitivity.Results:In this study,a total of 10 SNPs related to drug response were obtained by GWAS(p<1×10-4):rs10917694(p=1.42×10-5),rs12333877(p=3.27×10-5),rs10753608(p=4.13×10-5),rs2662776(p=4.13×10-5),rs4327910(p=5.85×10-5),rs10841845(p=6.23×10-5),rs28585512(p=7.17×10-5),rs4657248(p=8.98×10-5),rs7519727(p=8.98×10-5),rs6895277(p=9.57×10-5).Using RegulomeDB to predict the transcription factor binding site,we found that rsl2333877 was located at 4 transcription factor binding sites such as MAX;rs18585512 was located at 30 transcription factor binding sites such as NFKB1;rs7519727 was located at 15 transcription factor binding sites such as CCNT2.Using the UCSC genome browser to get data of histone modification and DNase I hypersensitive site,we found that two SNPs,rs7519727 and rs28585512,were at H3K4Mel and H3K27Ac regions and located at the DNase I hypersensitive site.The miRNA binding site of rs10841845 was predicted by PolymiRTS.It was found that the C allele derived from the ancestral allele T can bind to hsa-miR-6840-5p,resulting in a new miRNA binding site.Using GTEx for eQTL prediction,two SNP loci,rs4657248 and rs7519727,were found as the eQTL of RGS5 gene in the lung tissue.Using the GEO expression profile data,we explored the relationship between the expression of RGS5 gene and platinum sensitivity,and found that RGS5 gene was highly expressed in platinum-sensitive cells and lowly expressed in platinum-resistant cells.Conclusion:A genome-wide association analysis was performed on the response to platinum-pemetrexed in NSCLC patients and we obtained 10 SNPs associated with drug response such as rs 10917694(p<1×10-4).By integrating GWAS,functional prediction,eQTL analysis,and GEO expression profile data,we proposed that the rs7519727 G allele may affect the expression of RGS5 gene through transcriptional regulation,which in turn affects the response to platinum-pemetrexed.