TERT rs2853669 as a predictor for overall survival in patients with acute myeloid leukaemia.

INTRODUCTION: the aim of the study was to investigate the contribution of TERT rs2736100 and rs2853669 gene polymorphisms in defining the genetic predisposition to acute myeloid leukaemia (AML), their association with different prognostic markers, and their impact on survival, outcome, and the prognosis of affected patients. Also, we investigated the association of TERT SNPs in AML in the presence or absence of DNMT3A (R882), NPM1, and FLT3 mutations. MATERIAL AND METHODS: A total of 509 participants were enrolled in our study, consisting of 146 AML patients and 363 healthy participants, with no history of malignancy. TERT rs2736100 and rs2853669 polymorphisms were genotyped by using TaqMan SNP genotyping assay FLT3 (ITD, D835), DNMT3A (R882), and NPM1 c.863_864insTCTG (type A) mutations were analised in each AML case. RESULTS: TERT rs2736100 and rs2853669 were not associated with AML risk in the codominant, dominant, recessive, or allelic models. Multivariate Cox regression showed that TERT rs2853669 was a significant predictor for overall survival in AML patients. After adjusting for age, gender, cytogenetic risk group, ECOG status, FLT3, DNMT3A, NPM1 mutation, AML subtype, and treatment, the estimated adjusted hazard ratio (HR adjusted = 1.54, 95% CI: 1.01-2.35) showed that the TERT rs2853669 variant genotype had a negative influence on survival time. CONCLUSIONS: TERT rs2853669 and rs2736100 polymorphisms were not risk factors for developing AML in the Romanian population, but the TERT rs2853669 variant genotype had a negative effect on AML patients' overall survival in the presence of other known prognostic factors.

Presence of copy number aberration and clinical prognostic factors in patients with acute myeloid leukemia: an analysis of effect modification.

INTRODUCTION: Acute myeloid leukemia (AML) is characterized by multiple acquired genetic events, chromosomal abnormalities such as copy number aberrations (CNAs), disease progression, and low survival rates. OBJECTIVES: We assessed the utility of a multiplex ligation-dependent probe amplification (MLPA) assay in AML as well as correlations of CNAs with various biological and clinical features of patients with AML, including somatic mutations in the FLT3, NPM1, and DNMT3A genes and survival. PATIENTS AND METHODS: The study included 283 patients with AML. The MLPA was used for investigation of CNAs. The status of somatic mutations was analyzed in all cases. RESULTS: The presence of CNAs was associated with the adverse (high) risk category according to the European LeukemiaNet (ELN) classification (PFDR <0.0001). The significant predictors of mortality were age of 65 years or older (hazard ratio [HR], 2.30; 95% CI, 1.71-3.09), ELN high­risk category (HR, 1.71; 95% CI, 1.15-2.56), and the Eastern Cooperative Oncologic Group Scale (ECOG) performance status grade of 3 or higher (HR, 2.43; 95% CI, 1.80-3.30), but not the presence of CNA. An interaction between CNAs and the ECOG performance status was shown (HRinteraction, 2.24; 95% CI, 1.09-4.57, P = 0.02). The presence of CNAs was positively correlated with the risk of death in patients with an ECOG grade of 3 or higher (HR, 2.02; 95% CI, 1.30-3.12), while for patients with the performance status of 2 or lower, the presence of CNAs was a protective factor against the risk of death. CONCLUSIONS: The presence of CNAs may modify the effect of the ECOG performance status on survival. Independent predictors of mortality in patients with AML include age, ELN adverse risk category, and the ECOG grade of at least 3.

Cytokine rs361525, rs1800750, rs1800629, rs1800896, rs1800872, rs1800795, rs1800470, and rs2430561 SNPs in relation with prognostic factors in acute myeloid leukemia.

BACKGROUND: Cytokines were correlated with survival and disease progression in acute myeloid leukemia (AML). We aimed to evaluate the multivariate effect of TNF-α rs361525, rs1800750, rs1800629, IL-10 rs1800896, rs1800872, IL-6 rs1800795, TGF-ß1 rs1800470, IFN-γ rs2430561 single nucleotide polymorphisms (SNPs) on AML risk, the multivariate effect of SNPs on overall survival (OS) in AML and the association between the investigated SNPs and prognostic factors in AML. METHODS: All SNPs were genotyped in 226 adult AML cases and 406 healthy individuals. AML patients were investigated for FLT3 (ITD, D835), DNMT3A (R882), and NPM1 type A mutations. RESULTS: Univariate analysis revealed that age above 65 years had a negative influence on survival (P < .001). The presence of the rs1800750 variant genotype (P = .005) or FLT3-ITD mutation (P = .009) in a cytogenetic high-risk group (P = .003) negatively influenced OS. A negative association was observed between Eastern Cooperative Oncologic Group Scale status > 2, lactate dehydrogenase (LDH) level, platelet (PLT) count <40 000 cells/mm3 , and OS. Multivariate Cox regression analysis showed that the presence of the rs1800750 variant genotype was a risk factor for death (P = .007), and that blast percentage, LDH level (≥600 IU/L), and cytogenetic high-risk were independent significant predictors for death in AML (P = .04, corrected HR = 1.20; P = .022, corrected HR = 1.24; P = .021, corrected HR = 1.34, respectively). CONCLUSIONS: Age above 65 years, PLT count, TNF-α rs1800750 variant genotype, blast percentage, LDH level, and cytogenetic high-risk may be used as independent risk factors to assess AML mortality.