The Association Of UGT1A1~*28、~*6Gene Polymorphism With The Adverse Effects And Efficacy Of Irinotecan

Background and Objective:Drug genetic polymorphism mainly include drug metabolizing enzymes, receptors and targeting polymorphism, which leads to the individual differences in drug efficacy and adverse effects. Pharmacogenomics develops from drug genetic polymorphism, studying differences of gene sequences and their impacts on the efficacy and adverse effects to reveal the differences at the genetic level. Topoisomerase I inhibition-Inirotecan(CPT-11), which was used in the therapy of advanced colorectal cancer at first, nowadays has been widely used in other solid tumors, such as lung cancer, gastric cancer, cervical cancer, etc. Its side effect--delayed diarrhea limits its wider application. UGT1A1gene polymorphism was found to be associated with irinotecan chemotherapy-related toxicity.The purpose of this paper is to study UGT1A1*28、*6distribution in patients with malignant tumors and to explore its relationship with toxicity and efficacy of irinotecan.Methods:One hundred and twenty-two blood samples of the patients with malignancy treated with irinotecan in medical oncology department of the Second Affiliated Hospital of Zhejiang University from Jan.2010to Dec.2014were collected. The relationships of the UGT1A1*28、*6polymorphism with the adverse reactions and efficacy of irinotecan were analyzed.Results:1. The distribution of UGT1A1*28.*6genotypesAmong the122samples collected,90cases (73.77%) were the wild genotype TA6/6,29cases (23.77%) were heterozygous TA6/7and only3cases were homozygous mutant genotype TA7/7(2.46%).Besides,53cases(71.06%)were the wild genotype G/G,23cases (30.26%) were heterozygous G/A and0case was homozygous mutant genotype A/A of76samples tested with the*6genotype. Among the76samples tested with both*28and*6genotypes, there are three sorts according to the number of mutant foci:wild type (TA6/6&G/G), single focus mutant (TA6/7&G/G、TA6/6&G/A) and two-foci mutant (TA6/7&G/A、TA7/7&G/G、TA6/6&A/A),which consists of56.58%(43cases),35.53%(27cases) and7.89%(6cases) respectively.2. The occurrence of adverse reactions23of93cases (24.73%) had delayed diarrhea, among which18cases (19.35%) were degree Ⅰ-Ⅱ and5cases(5.38%) were degree Ⅲ-Ⅳ. Neutropenia occurs in63cases (67.74%), with46cases (43.30%) degree Ⅰ-Ⅱ and17cases(18.28%) degree Ⅲ-Ⅳ.3. The relationship between UGT1A1genotypes and adverse reactionsThe incidence rate of overall neutropenia in patients with genotypes TA6/7、TA7/7was higher than that in patients with wild genotype TA6/6(91.67%vs59.42%,P=0.004);(37.5%vs20.29%, P=0.039) and so was degree Ⅲ-Ⅳ delayed diarrhea (16.67%vs1.45%, P=0.004). The incidence rate of degree Ⅲ-Ⅳ neutropenia in patients with genotypes G/A、A/A was higher than that in patients with wild type G/G was (25.0%vs5.71%, P=0.047). The incidence rate of degree Ⅲ-Ⅳ delayed diarrhea in patients with single focus mutant and two-foci mutant types (TA6/6&G/A、TA6/7&G/G、TA6/6&A/A、TA7/7&G/G、TA6/7&G/A)was higher than that in patients with wild genotype (TA6/6&G/G)(13.64%vs0.0%, P=0.040). The incidence rate of degree Ⅲ-Ⅳ delayed diarrhea in patients with two-foci mutant types (TA6/6&A/A、 TA7/7&G/G、TA6/7&G/A) was higher than that in patients with wild genotype (TA6/6&G/G)(25%vs0.0%, P=0.006).4. The relationship between UGT1A1genotypes and efficacy76cases were evaluated for efficacy,which included0CR,8PR,28SD and40PD, leading to the effective rate10.53%, disease control rate47.37%, among which the effective rate of first-line therapy is17.65%, disease control rate73.53%, the effective rate of second-line therapy is3.85%, disease control rate34.62%. There was no significant difference in Objective Response Rates (10.53%vs10.53%) and Disease Control Rates (45.61%vs52.63%) between wild type TA6/6and mutant types TA6/7、TA7/7. There was either no significant difference in Objective Response Rates (10.0%vs14.29%) and Disease Control Rates (46.67%vs35.71%) between wild type G/G and mutant types G/A、A/A. There was either no significant difference in Objective Response Rates (10.34%vs9.09%) and Disease Control Rates (48.28%vs45.45%) between wild type (TA6/6&G/G) and single focus mutant and two-foci mutant types (TA6/6&G/A、TA6/7&G/G、TA6/6&A/A、TA7/7&G/G、TA6/7&G/A)Conclusions:1.Among UGT1A1*28genotypes, wild type TA6/6is the most common one, then is heterozygous mutant type TA6/7, homozygous mutant type TA7/7is the most uncommon. Among UGT1A1*6genotypes, wild type G/G is the most common one, then is heterozygous mutant type G/A, homozygous mutant type A/A is not found in this study. Wild type is the most common one, single focus mutant types are the second common ones while two-foci mutant types are the least common ones when combining UGT1A1*28genotypes with*6genotypes.2.Compared with people with wild type TA6/6, patients with mutant types TA6/7、 TA7/7have a higher incidence rate of degree Ⅲ-Ⅳ delayed diarrhea and overall neutropenia when treated with irinotecan. Compared to people with wild type G/G, patients with mutant types G/A、A/A have a higher incidence rate of degree Ⅲ-Ⅳ neutropenia when treated with irinotecan. Compared with people with wild type (TA6/6&G/G), patients with mutant types (TA6/6&G/A、TA6/7&G/G、TA6/6&A/A、 TA7/7&G/G、TA6/7&G/A) have a higher incidence rate of degree III-IV delayed diarrhea when treated with irinotecan. Compared with people with wild type (TA6/6&G/G), patients with two-foci mutant types (TA6/6&A/A、TA7/7&G/G、TA6/7&G/A) have a higher incidence rate of degree III-IV delayed diarrhea when treated with irinotecan.3. The polymorphisms of UGT1A1*28、*6shows no relevance with the efficacy of irinotecan.