| Objective:(1)To study the genotype distribution of single nucleotide polymorphisms (SNP) in genes related to drug metabolizing and transporting enzymes in patients with de novo acute myeloid leukemia (AML).(2)To investigate the differences among multiple genotypes of SNP sites referring to the complete remission (CR) rate of induction chemotherapy, refractoriness, relapsing rates and survival of AML.(3)To detect the independent risk factors associated with achievement of CR, refractoriness, relapse and clinical prognosis of survival in patients with de novo acute myeloid leukemia.Methods:113 samples of patients with de novo AML were collected. The genotypes of 14 SNP of genes related to drug metabolizing (CYP2D6, CYP1A1, CYP2C19. CYP3A5, POR, NAT2, UGT1A1, DPYD, GSTA1, GSTO1, GSTO2, GSTP1) and transporting (ABCB1, SLC22A1) enzymes were detected by the SNPstream(?) Genotyping System. The frequency of genotypes and alleles in separate SNP was computed statistically in AML patients. Logistic regression analysis was applied to detect risk factors associated with achievement of CR, refractoriness and relapse in AML patients. The overall survival (OS) and disease-free survival (DFS) rate was analyzed by Kaplan-Meier methods. The differences among distinct groups were compared by log-rank test. Cox's proportional hazard model was applied to analyze the independent prognostic factors.Results:1. All the SNP of genes were in accordance with Hardy-Weinberg equilibrium except for CYP2D6.2. SNP of CYP2D6, GSTO2 and NAT2 were independent factors associated with achievement of CR after first course of chemotherapy. The favorable factors include homozygote AA or heterozygote AG of NAT2 (RR=2.73, P=0.039) and heterozygote TC of GSTO2 (RR=3.55, P=0.006). Meanwhile, the unfavorable factor was heterozygote AG of CYP2D6 (RR=0.31, P=0.03).3. SNP of CYP3A5 and POR, karyotype and 1st induction chemotherapy were independent factors associated with achievement of CR after two course of chemotherapy. The favorable factors include heterozygote TC of POR (RR=13.38, P=0.006), chemotherapy with triple drugs in first course (RR=8.78, P=0.006). Meanwhile, the unfavorable factors include homozygote AA of CYP3A5 (RR=0.067, P=0.012) and high risk karyotype according to cytogenetics (RR=0.031, P=0.004).4. SNP of ABCB1 and age were important factors associated with refractoriness and relapse. Homozygote TT of ABCB1 was the protective factors independently for decreasing the risk rate of refractoriness (RR=0.079, P=0.027) and relapse (RR=0.077, P=0.025) in de novo AML patients. Age over 40 years old independently increased risk of refractoriness (RR=3.41, P=0.027), but did not associated with relapse.5. SNP of POR, GSTP1 and CYP3 A5, smoking history, karyotype, sex and HSCT were important predictors for prognpsis of survival. Independently adverse prognostic factors for overall survival include smoking history (RR=2.50, P=0.018) and homozygote TT of POR (RR=2.62, P=0.049). Independently adverse prognostic factors for disease-free survival include homozygote GG of GSTP1 (RR=11.50, P-0.006), homozygote AA of CYP3A5 (RR=3.05, P=0.011), high risk karyotype (RR=9.41, P=0.001) and male patients (RR=2.50, P=0.019). Patients who experienced hematopoietic stem cell transplantation (HSCT) were favorable prognostic factor for OS (RR=0.24, P=0.018) and DFS (RR=0.11, P=0.000).6. SNP of NAT2, CYP3A5 and ABCB1, age and karyotype were important predictors for prognosis of chemotherapy survival. Homozygote AA or heterozygote AG of NAT2 was the only protective factors for overall survival of chemotherapy independently (RR=0.34, P=0.043). Independently adverse prognostic factors for overall survival of chemotherapy include homozygote AA of CYP3A5 (RR=2.74, P=0.022), age over 40 years old(RR=2.61, P=0.006)and high risk karyotype (RR=6.17, P=0.007). Favorable prognostic factors include homozygote TT of ABCB1 (RR=0.19, P=0.031), homozygote AA or heterozygote AG variant genotype of NAT2 (RR=0.45, P=0.048).7. There was no association between SNP of CYP1A1, CYP2C19, UGT1A1, DPYD, GSTA1, GSTO1, SLC22A1 and achievement of CR, refractoriness, relapse and prognosis. Conclusion:Seven SNP of CYP2D6, GSTO2, NAT2, CYP3A5, POR, ABCB1 and GSTP1 were associated with achievement of CR, refractoriness, relapse and survival of de novo AML. SNP of CYP2D6, GSTO2, NAT2, CYP3A5 and POR, karyotype and 1st induction chemotherapy were independent risk factors of achievement of CR. SNP of ABCB1 and age were independent factors of refractoriness, while SNP of ABCB1 was also independent factors of relapse. The independent predictors for prognosis of survival include SNP of POR, GSTP1 and CYP3A5, smoking history, karyotype, sex and HSCT. The independent predictors for prognosis of chemotherapy survival were SNP of NAT2, CYP3A5, ABCB1 and NAT2, age and karyotype. According to the genotype of SNP above, we could give important information for achievement of CR, refractoriness, relapse and survival, and discriminite the high risk group, which were prescribed high intensity chemotherapy or HSCT. It could provide new strategies for research of drug resistance mechanism, predication of treatment efficacy and administration of personalized treatment. |
