Abstract
Telomerase reverse transcriptase gene (TERT) promoter mutations are identified in many malignancies but not in hematological malignancies. Here we analyzed TERT and protection of telomeres 1 gene (POT1) mutations, and four different TERT SNVs in 226 acute myeloid leukemia (AML) patients and 806 healthy individuals in a case referent design, where also overall survival was assessed. A significant association for increased risk of AML was found for TERT SNVs, rs2853669 (OR = 2.45, p = 0.00015) and rs2736100 (OR = 1.5, p = 0.03). The overall survival for patients with CC genotype of rs2853669 was significantly shorter compared to those with TT or TC genotypes (p = 0.036 and 0.029 respectively). The influence of TERT rs2853669 CC on survival was confirmed in multivariable Cox regression analysis as an independent risk biomarker in addition to high risk group, higher age and treatment. No hot spot TERT promoter mutations at -228C > T or -250C > T or POT1 mutations could be identified in this AML cohort. We show that rs2853669 CC may be a risk factor for the development of AML that may also be used as a prognostic marker to identify high risk normal karyotype-AML (NK-AML) patients, for treatment guidance.
Highlights
It is estimated that more than 90% of all cancers have increased telomerase activity [1] which correlates with immortalization, resistance to senescence and apoptosis, and telomere elongation
Telomerase reverse transcriptase gene (TERT) 1062A> T that has been identified as a susceptibility mutation in an Egyptian acute myeloid leukemia (AML) population, was found in 10/249 patients (4%) and in 22 of 806 healthy control (2.7%), (OR = 1.47, 95% confidence intervals (CI) 0.68–3.14, p = 0.21)
Genotyping of the four single nucleotide variants (SNVs) in the TERT gene in this study, revealed an increased risk for AML of the rs2853669 CC genotype (OR = 2.45, 95% CI 1.54–3.88, p = 0.00015) (Table 1)
Summary
It is estimated that more than 90% of all cancers have increased telomerase activity [1] which correlates with immortalization, resistance to senescence and apoptosis, and telomere elongation. Up regulation of TERT expression is abundantly reported in somatic cells and two hot spot mutations in the TERT promoter, -228C > T and -250C > T, were recently reported in several different solid tumors e.g melanoma and gliomas [3,4,5,6]. These mutations have strong clinical implications with worse prognosis and poor survival and may represent a novel therapeutic target [6]. POT1 loss-of-function mutations are prevalent in familial melanoma [11]
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