Genetic Susceptibility And Prognostic Factors Of Chinese De Novo Inv(16)/t(16;16)/CBFβ-MYH11(+) Acute Myeloid Leukemia

ObjectiveTo investigate the impact of polymorphisms in DNA homologous recombination repair genes RAD51-G135C and XRCC3-Thr241Met on the genetic susceptibility of Chinese de novo inv(16)/t(16;16)/CBFβ-MYHII(+) acute myeloid leukemia (AML).MethodsGenomic DNA was extracted from bone marrow cells in 625 de novo AML patients and from peripheral blood cells in 806 families of patients and 704 unrelated volunteers. The 625 de novo AML patients consisted of 105 AML patients with inv(16)/t(16;16)/CBFβ-MYHll, 111 with t(15;17)/PML-RARA,151 with t(8;21)/AML1-ETO,12 with 11q23,91 with cyto-genetics abnormality (excluding above four AML subtypes), and 155 with cytogenetics normal. Genotypes of RAD51-G135C and XRCC3-Thr241Met were analyzed by PCR-RFLP.ResultsThe XRCC3-241Met variant(Thr/Met+Met/Met) increased the risk of developing AML in total AML patients, both versus the volunteer controls (OR=1.67; 95%CI,1.20-2.27; p=0.007) and versus the family controls (OR=1.50; 95%CI,1.10-2.03;p=0.009). The XRCC3-241Met variant 7.22-fold (95%CI,4.37-11.91; p<0.001) increased the risk of developing of the AML with inv(16)/t(16;16)/CBFβ-MYHII when as compared with the volunteer controls, and 7.99-fold (95%CI,5.03-12.69;p<0.001) increased when as compared with the family controls. Conversely, the XRCC3-241Met variant reduced the risk of developing of the AML with t(15;17)/PML-RARA compared with the volunteer controls (OR = 0.35; 95%CI,0.13-0.90;p=0.030). The XRCC3-241Met variant had no influence on the risk of developing AML in other AML subtypes. The RAD51-135C variant (G/C+C/C) had no influence on the risk of developing AML, either in the total AML or in the AML with inv(16)/t(16;16)/CBFB-MYHII or in other AML subtypes.Furthermore, the multivariate analysis (variables including age, gender, RAD51 variant and XRCC3 variant) and stratified analysis were showed that the XRCC3-241Met variant increased the risk of the AML with inv(16)/t(16;16)/CBFβ-MYHII but reduced the risk of the AML with t(15;17)/PML-RARA.ConclusionThe XRCC3-241Met variant genotype is an independent genetic susceptible factor for the AML with inv(16)/t(16;16)/CBFβ-MYHII. The occurrence of inv(16)/t(16;16)/CBFβ-MYHII may be associated with the dysfunctional DNA homologous recombination repair mechanism. ObjectiveTo investigate the role of the genotype in DNA homologous recombination gene XRCC3-Thr241Met on the occurrence of CBFβ-MYHII fusion gene.MethodsThe KG1a cell line with XRCC3-Thr241Met wild-type and HL-60 cell line with XRCC3-Thr241Met homozygote-type were selected. The RAD51-G135C genotype was wild-type in the KG1a cell line and HL-60 cell line. Cell line was irradiated by 50Gy doses of y-irradiation, then cultured for 24 hours; which was named as irradiated group. Cell line was cultured for 24 hours, but not irradiated by y-irradiation, which was named as control group. The CBFβ-MYHII fusion gene was detected by FISH and real-time PCR. The CBFβ-MYHII mRNA level was compared between KGla cell line and HL-60 cell line.ResultsIn HL-60 cell line, the CBFβ-MYHII mRNA level of the irradiated group was increased 27.52 times as compared with the control group. In KGla cell line, the CBFβ-MYHII mRNA level in the irradiated group was increased 5.73 times versus the control group. The CBFβ-MYHII mRNA level in the control group of HL-60 cell line was increased 12.38 times as compared with the control group of KG1a cell line. The CBFβ-MYHII mRNA level in the irradiated group of HL-60 cell line was increased 59.49 times versus the irradiated group of KG1a cell line. The FISH test of the CBFfβ-MYHII fusion gene was negative in the control group and irradiated group of HL-60 cell line or in the control group and irradiated group of KG1a cell line.ConclusionThe XRCC3-Thr241Met homozygote-type is remarkably increased the risk of the occurrence in the CBFβ-MYHII fusion gene. The occurrence of the CBFβ-MYHII fusion gene may be associated with the dysfunction of DNA homologous recombination repair mechanism. ObjectiveTo investigate the prognostic factors of Chinese de novo inv(16)/t(16;16)/CBFβ-MYHII (+) acute myeloid leukemia (AML). Especially, to investigate whether the polymorphisms of DNA homologous recombination repair genes RAD51-G135C and XRCC3-Thr241Met could influence prognosis of patients with this disease.MethodsOne hundred and three patients with valid results of chromosomal karyotype and successfully follow-up were retrospectively analyzed. Polymorphisms of RAD51-G135C and XRCC3-Thr241 Met were detected by PCR-RFLP. The prognostic factors for complete remission (CR) achievement, overall survival (OS) and relapse-free survival (RFS) of patients were analyzed by univariate analysis and multivariate analysis.ResultsAmong the 103 patients,48 died. The median follow-ups of all patients and survival patients were 28 (range,1-106) and 46 (range,7-106) months, respectively. The overall CR rate was 92.2%. The estimated 5-year OS and estimated 5-year RFS were 43.6%(95%CI, 37.7%-49.5%) and 26.4%(95% CI,21.1%-31.7%), respectively. The median OS times and median RFS times were 53 (95% CI,33.4-72.7) and 27 (95% CI,22.9-31.1) months, respectively. In multivariate analysis:higher WBC (p=0.003, when considered as a continuous variable) and older age (p=0.035, when considered as a categoric variable with an age cutpoint at 30 years) were two independent bad-prognosis factors for CR achievement, the XRCC3-241Met variant (p=0.006) and higher WBC (p=0.011, when considered as a continuous variable) were two independent bad-prognosis factors for 5-year RFS, higher WBC (p=0.003, when considered as a continuous variable) and cytogenetics abnormality with an associated trisomy 8 (p=0.030) were two independent bad-prognosis factors for 5-year survival. But, the polymorphism of RAD51-G135C had no significant impact on the prognosis of patients.ConclusionsHigher WBC and XRCC3-241Met variant are two independent bad-prognosis factors for the AML with inv(16)/t(16;16)/CBFβ-MYH11. The cytogenetics abnormality with an associated trisomy 8 may be an independent bad-prognosis factor for this AML subtype.