Correlation Study Of TPMT Gene Polymorphism And 6-MP Metabolismininacute Lymphoblastic Leukemia In Children

Objective:To study the types of mutations and the frequency of mutations in thi-opurine S-methyltransferase (TPMT) in children with acute lymphoblastic leukemia(ALL) in Kunming Children's Hospital, Kunming Medical University,And through retrospective analysis of ALL children during maintenance treatment of the correspo-nding clinical data,to investigate the relationship between TPMT gene polymerphism and the adverse reactions caused by 6-mercaptopurine(6-mercaptopurine, 6-MP),in order to further guide the clinical application of mercaptopurine, and to provide a new theoretical basis for the individual treatment of children with ALL.Methods :Usingpolymer-specific PCR (AS-PCR) and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP)methods to detect the common TPMT mutant alleles with Gene TPMT* 2 (G238C), TPMT * 3B (G460A)and TPMT * 3C (A719G) mutationsin 93 newly diagnosed ALL patients. To analyze the relationship of adverse reactionsbetweenits TPMT gene polymorphism and the adversereactions that were caused by 6-MP during maintain chemotherapy.Results: 1.There were 2 cases of TPMT * 3C genotype mutationin 93 children with ALL, and the mutation rate was 2.15% (2/93). All of them were heterozygous mutations. The allele mutation frequency was 1.08% No mutations in TPMT * 2, * 3B genes were detected.2. The cumulative treatment time of 6-MP in ALL patients during the period of chemotherapy was 336.5 days (55 to 663 days), 31.71% of children (26/82) were discontinued due to 6-MP severe adverse events,and the average number of days of withdrawal was 8 days (2 to 21 days);Among the children who discontinued, the proportion of secondary infection was 24.39% (20/82), 7 of them were infused with erythrocytes and 4 were transfused with platelets.3.In the 6-MP adverse reactions, the proportion of leukopenia was 57.32% (47/82),neutrophils was 59.76% (49/82), hemoglobin decline was 58.54% (48/82),thrombocytopenia was 29.27% (24/82), alanine aminotransferase increased was 42.68% (35/82), aspartate aminotransferase increased was 29.27% (24/82), direct bilirubin was 10.98% (9/82), gastrointestinal was 12.20% (10 / 82).4.In the 6-MP adverse reactions, leukopenia, neutropenia, hemoglobin decreased,thrombocytopeniaand elevated transaminase arethe common adversereactions.Which white blood cells and neutropenia mainly for severe adverse reactions,the others are mild adverse reactions.5.Two cases of TPMT * 3C genotype mutations in the ALL children had a serious adverse reaction,who had a significant 6-MP dose intolerance,and there are still leukopenia, neutropenia when taking a 1/6 standard dose.Conclusions:1. There were 2 cases of TPMT * 3C genotype mutations in all ALL children.2. During the 6-MP maintenance treatment, The most important recent adverse reactions were myelosuppression,mainly lead to leukopenia and neutropenia, the incidence was 57.32%, 59.76%.3. The sensitivity and positive rate of the TPMT * 3C genotype mutations are low,It is not suitable for the Chinese population as a 6-MP adverse reaction related to the detection gene, we should continue to look for other genes suitable for the Chinese population.4. Study has been found that TPMT * 3, TPMT * 3A, TPMT * 3B and TPMT *3C are the most common type of genotype mutations, In this study, only TPMT * 3C genotype mutations were found, and this genotype mutation was closely related to 6-MP intolerance.