Abstract 3518: TP53 mutations and MDM2 single nucleotide polymorphism 309T-G predicts outcome and treatment resistance in acute myeloid leukemia
Authors: Falk Ingrid Jakobsen , Willander Kerstin , Chaireti Roza , Lund Johan , Hermanson Monica , Greén Henrik , Söderkvist Peter , Lotfi Kourosh 
Published: May 2015

Abstract
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&gt;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&lt;0.001). TP53mut patients had markedly lower response rates compared to TP53 wild-type (wt) patients (21% and 76% CR, respectively, p&lt;0.001) and a significantly reduced OS (5 and 21 months, respectively, p&lt;0.001). In TP53wt patients with abnormal karyotype, the MDM2SNP309 conferred an impaired outcome, with patients carrying the alternative G allele having shorter OS compared to T/T patients (13 and 29 months, p=0.031). This effect was neither observed in OS analysis of the entire group, nor in the normal karyotype patients, suggesting that the SNP G-allele carriers may suppress function of wild-type p53 in cytogenetically altered tumors. Allo-SCT in first complete remission improves the prognosis in AML patients with intermediate or high risk. However, some patients, including those with monosomal karyotype, and, as seen in our study, patients with TP53mut, are unlikely to reach CR with standard treatment. These patients may be considered for clinical trials with emerging novel therapies targeting the p53 signaling pathway. In conclusion, our results show that TP53mut identifies a subgroup of AML patients with dramatically impaired outcome. TP53 analysis, and potentially also MDM2SNP309 genotyping, should be implemented in prognostication, risk stratification and selection of patients most likely to benefit from new drugs such as the nutlins (MDM2-inhibitors) and PRIMA-1 (“p53 Reactivation and Induction of Massive Apoptosis”).
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