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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 SNPs in 256 acute myeloid leukemia (AML) patients. A significant association for increased risk of AML was found for TERT SNPs, rs2853669 (OR = 2.45, p = 0.00006) and rs2736100 (OR = 1.52, p = 0.02). 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, 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 for the first time that rs2853669 CC may be a risk factor for the development of AML that may also be used as a prognostic marker to identify relative high risk NK-AML patients, for treatment guidance. Note: This abstract was not presented at the meeting. Citation Format: Kourosh Lotfi, Mohamed Ali Mosrati, Kerstin Willander, Ingrid Jakobsen Falk, Monica Hermanson, Martin Höglund, Dick Stockelberg, Yuan Wei, Peter Söderkvist. Association of TERT polymorphism with acute myeloid leukemia risk and prognosis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5275. doi:10.1158/1538-7445.AM2015-5275

The tumor-suppressor gene TP53, encoding the p53 protein, is vital for normal cellular processes including cell cycle regulation, apoptosis and senescence. Mutations in TP53 are frequent in many cancers, and have been associated with treatment resistance and inferior prognosis in acute myeloid leukemia (AML). Altered expression of MDM2 (mouse double minute 2), a negative regulator of p53, may also attenuate normal p53 signaling, thereby enhancing tumor transformation and resistance to apoptosis. The single nucleotide polymorphism (SNP) 309 (T>G, rs2279744) has been reported to increase MDM2 expression and impair normal p53 response. We investigated the frequency and impact of TP53 mutations (TP53mut) and MDM2SNP309 on treatment response and overall survival (OS) in 207 Swedish AML patients. To detect the TP53mut in exons 5-8, the single strand conformation analysis (SSCA) was performed. Samples with mobility shift were sequenced to determine the exact nucleotide sequence and compared to the corresponding TP53 reference sequence (NM_000546.4). MDM2SNP309 was analyzed using Pyrosequencing. We found a high frequency (22%) of TP53mut in patients with cytogenetic aberrations, with strong association to high risk cytogenetics (p Citation Format: Ingrid Jakobsen Falk, Kerstin Willander, Roza Chaireti, Johan Lund, Monica Hermanson, Henrik Greén, Peter Söderkvist, Kourosh Lotfi. TP53 mutations and MDM2 single nucleotide polymorphism 309T-G predicts outcome and treatment resistance in acute myeloid leukemia. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3518. doi:10.1158/1538-7445.AM2014-3518

Background: De novo AML with normal karyotype (NK-AML) comprise a large group of patients without common cytogenetic alterations but with a large variation in treatment response. New tools such as the analysis of nucleophosmine 1 (NPM1), FMS-like tyrosine kinase 3 (FLT3) and CCAAT/enhancer binding protein (CEBPA) mutations has emerged as clinical markers of prognosis, but there is still a need for additional tools to explain the variation in outcome. Cytarabine (Ara-C), a cornerstone in AML chemotherapy, is activated intracellularly by deoxycytidine kinase (dCK), and deactivated by cytidine deaminase (CDA) and poor treatment outcome or development of chemotherapy resistance can be due to altered activity of these enzymes. Single nucleotide polymorphisms (SNPs) of CDA genes have previously been reported to result in lower CDA allelic expression and to affect the outcome of treatment. In addition, pharmacological inhibition of CDA has been shown to reduce the degree of DNA methylation. DNA methylation may be an important regulatory mechanism for the expression of genes related to drug effect, and we therefore aimed to investigate the relationship between CDA polymorphisms and outcome in NK-AML, DNA methylation, and in vitro drug cytotoxicity. Method: 207 Swedish NK-AML patients were genotyped for the CDA SNPs 79A>C (rs2072671) and -451C>T (rs532545) and the results were correlated to treatment response and overall survival (OS) in the material as a whole as well as stratified based on FLT3 and NPM1 status. Cells from a subset of the patients were also investigated for genotype association with in vitro drug cytotoxicity (n=56) and global DNA methylation (n=82). Results: CDA 79C/C or -451T/T genotype was associated to a shorter OS compared to other genotypes (0.44 vs. 1.86 years, p=0.004; and 0.45 vs. 1.79 years, p=0.051) for FLT3-ITD+ patients, and this was even more pronounced in the FLT3-ITD+/NPM1+ cases. There was significantly less DNA methylation in cells heterozygous for both polymorphisms (A/C+C/T) compared to homozygous A/A+C/C cells (p=0.018). There was also a lower degree of methylation in homozygous C/C+T/T cells, but due to the small number of samples in this group significance was not reached. An altered in vitro sensitivity towards topoisomerase inhibitory drugs, but not towards nucleoside analogues was seen for both CDA SNPs with homozygous C/C or T/T cells being more sensitive. Conclusions: We found a significant correlation between CDA genotype and OS in NK-AML, the degree of DNA methylation in AML cells, and in vitro drug sensitivity. The change in methylation related to CDA genotype may be associated with differences in drug activation and subsequent sensitivity, making these polymorphisms potential markers of use for future individual chemotherapy decisions such as dose adjustments. Citation Format: Ingrid Jakobsen Falk, Anna Fyrberg, Monica Hermanson, Martin Höglund, Hareth Nahi, Lars Palmqvist, Christer Paul, Esbjörn Paul, Richard Rosenquist, Dick Stockelberg, Yuan Wei, Henrik Green, Kourosh Lotfi. Correlation between cytidine deaminase single nucleotide polymorphisms and in vitro drug sensitivity, DNA methylation and outcome in normal karyotype acute myelogenous leukemia. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1170. doi:10.1158/1538-7445.AM2013-1170