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TP53 mutations and MDM2(SNP309) identify subgroups of AML patients with impaired outcome
Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.ORCID iD: 0000-0003-4450-0333
Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Acute Internal Medicine. Karolinska University Hospital, Sweden.
Huddinge University Hospital, Sweden.
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2015 (English)In: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609, Vol. 94, no 4, 355-362 p.Article in journal (Refereed) Published
Abstract [en]

BackgroundTP53 is commonly mutated in several cancers and confers treatment resistance and poor prognosis. Altered expression of mouse double minute 2 (MDM2), 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 has been reported to increase MDM2 expression and impair normal p53 response. Experimental designWe investigated the frequency and impact of TP53 mutations (TP53mut) and MDM2(SNP309) on treatment outcome and overall survival (OS) in 189 Swedish acute myeloid leukemia patients. The genetic analyses were performed using SSCA and direct sequencing (for mutations in exon 5-8 of TP53) and Pyrosequencing (for the MDM2(SNP309)). ResultsWe found a high frequency (22%) of TP53mut in patients with cytogenetic aberrations, with association to high-risk cytogenetics (Pless than0.001). TP53mut patients had lower response rates (22% compared with 76% CR in TP53 wild-type (wt) patients, Pless than0.001) and reduced OS (2 and 16months, respectively, Pless than0.001). In TP53wt patients with high or intermediate risk cytogenetic aberrations, the MDM2(SNP309) conferred an impaired outcome, with patients carrying the alternative G-allele having shorter OS compared with T/T patients (median 9 vs. 50months, P=0.020). ConclusionsOur results show that TP53mut analysis and MDM2(SNP309) genotyping may be useful tools for prognostication, risk stratification, and selection of patients most likely to benefit from new drugs targeting the p53 signaling pathway.

Place, publisher, year, edition, pages
Wiley: 12 months , 2015. Vol. 94, no 4, 355-362 p.
Keyword [en]
acute myeloid leukemia; TP53; MDM2; SNP309; prognostic markers
National Category
Clinical Medicine
URN: urn:nbn:se:liu:diva-117209DOI: 10.1111/ejh.12438ISI: 000351628000011PubMedID: 25156865OAI: diva2:807231

Funding Agencies|County Council of Ostergotland; AFA Insurance; Swedish Cancer Society; Stockholm Cancer Society; Karolinska Institutet; Swedish Research Council

Available from: 2015-04-23 Created: 2015-04-21 Last updated: 2016-02-19

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Jakobsen Falk, IngridWillander, KerstinChaireti, RozaLotfi, KouroshSöderkvist, Peter
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Division of Drug ResearchFaculty of Health SciencesDivision of Cell BiologyDepartment of HaematologyDivision of Microbiology and Molecular MedicineDepartment of Acute Internal MedicineDepartment of Clinical Pathology and Clinical Genetics
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