Single Nucleotide Polymorphisms Of Capecitabine Metabolic Enzyme Are Predictors Of Therapeutic Safety

BackgroundCapecitabine is an oral 5-fluorouracil(5-FU)prodrug.It is used as a first-line chemotherapy drugs for colorectal cancer because of its small toxicity,significant efficacy and convenient administration.However,about 30%of the patients still have restricted toxic effects,such as hand foot syndrome,diarrhea,neutropenia,and other restrictive toxic effects at the standard dose.It is an urgent problem in the clinical application of Capecitabine that to predict and inhibit the occurrence of toxic effects,to establish individualized scheme and to improve the safety of treatment.Pharmacogenomics research shows that,individual genetic variation is the main reason for the difference of adverse drug reactions,the enolase superfamily member 1(ENOSF1)and Cytidine Deaminase(CDA)are the key enzymes of capecitabine's metabolism,It's possible that ENOSF1 gene and CDA gene polymorphism are associated with the occurrence of Capecitabine adverse reactions.ObjectiveTo evaluate the relationship between Single nucleotide polymorphisms of enolase superfamily member1(ENOSF1)and Cytidine Deaminase(CDA)and Capecitabine related toxic effects and to explore its predictive value of Capecitabine safety.To provide a theoretical basis for the clinical safety of capecitabine,and to further guide the individualized medication.MethodsA total of 62 cases of primary colorectal cancer patients was collected from Gastroenterology and gastrointestinal surgery in the Henan Province People's Hospital In June 2016-June 2017,all of these patients accept Capecitabine alone or combined with chemotherapy,their demographic and histological data were collected,the genome DNA was extracted from the peripheral venous blood in each cycle of chemotherapy before,target gene was amplified through PCR(Polymerase Chain Reaction),and ENOSF1 single nucleotide polymorphisms rs2612091,IVS10-61 C>T,IVS10-60G>A,rs1059394genotype were detected by sequencing analysis;CDA single nucleotide polymorphisms rs532545 and rs3215400 genotype were detected by sequencing analysis;the toxic effects of 62 patients with the treatment of Capecitabine were recorded and the toxic effects between different genotypes were compared through combining clinical data.Results(1)The distribution of the genotypes in 62 colorectal cancer patients was as follows:rs2612091 wild-type A/A(18,37.5%),heterozygous mutant type A/G(26,54.2%),and homozygous mutant type G/G(4,8.3%),Minor Allele Frequency(MAF)G=0.3542,Global MAF G=0.3494;IVS10-61C>T wild-type C/C(23,47.9%),heterozygous mutant type C/T(20,41.7%),and homozygous mutant type T/T(5 10.4%),Minor Allele Frequency(MAF)T=0.3125;IVS10-60G>A wild-type G/G(25,52.1%),heterozygous mutant type A/G(17,35.4%),and homozygous mutant type A/A(6,12.5%),Minor Allele Frequency(MAF)A=0.3021;rs1059394 wild-type A/A(25,40.3%),heterozygous mutant type A/G(33,53.2%)and homozygous mutant type G/G(4,6.5%),Minor Allele Frequency(MAF)G=0.3306,Global MAF A=0.4978.The distribution of the genotypes in 62 colorectal cancer patients was as follows:rs532545 wild-type G/G(50,80.6%),heterozygous mutant type A/G(12,19.4%),the homozygous mutant type was not detected,Minor Allele Frequency(MAF)A=0.068,Global MAF A=0.1861;rs3215400 wild-type-/-(18,29.0%),heterozygous mutant type-/C(30,48.4%),and homozygous mutant type C/C(14,22.6%),MAF C=0.468,Global MAF C=0.4595.(2)According to the genotypes of patients,they were divided into three groups:wild-type,heterozygous mutant type and homozygous mutant type;according to the level of toxic effects,the patients were divided into two groups:grade 0~1 and grade 2~4;the relationship between genotypes and toxic effects was analyzed based on dominant and recessive models,and OR values and 95%confidence intervals were calculated.In dominant model,the risk of 2~4 hand-foot syndrome(HFS)in IVS10-60G>A G/G genotype was significantly higher than that of A/G and A/A genotype,and the difference was statistically significant(?~2=5.421,P=0.020,OR=4.364 95%CI:1.217-15.641);the risk of 2~4 hand-foot syndrome(HFS)in rs532545 AG genotype was significantly higher than that of GG genotype,and the difference was statistically significant(P=0.013 OR=1.56395%CI:1.269-1.924);the risk of 2~4 HFS in rs3215400-/-genotype was significantly higher than that of-/C and C/C genotype,and the difference was statistically significant(P=0.022 OR=10.704 95%CI:1.303-87.943).in recessive model,the risk of 2~4 diarrhea in IVS10-61C>T T/T genotype was significantly higher than that of C/C and C/T genotype,and the difference was statistically significant(Fisher's exact test P=0.817 OR=0.10895%CI:0.015-0.788);the risk of 2~4 neutropenia in rs3215400 C/C genotype was significantly higher than that of-/-and-/C genotype,and the difference was statistically significant(P=0.038 OR=0.278 95%CI:0.080-0.967).Conclusion(1)The mutation rate of ENOSF1 gene rs2612091 loci in Han population is slightly higher than that of other ethnic groups,and the mutation rate of rs1059394 loci is lower than that of other ethnic groups;The CDA rs3215400 mutant-type genotypes was much common compared with the rs532545 in Han patients.(2)ENOSF1 gene IVS 10-60G>A wild-type and IVS10-61C>T homozygous mutant type had increased risk of serious toxic effects;CDA gene rs532545 heterozygous mutant type?rs3215400 wild-type and rs3215400 homozygous mutant type had increased risk of serious toxic effects.ENOSF1 gene and CDA gene are expected to be used as genetic markers to predict the therapeutic safety of Capecitabine treatment.