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Next Generation Sequencing for the Detection of Actionable Mutations in Solid and Liquid Tumors
Published on: September 20, 2016
TP53 mutations and MDM2(SNP309) identify subgroups of AML patients with impaired outcome
Ingrid Jakobsen Falk1, Kerstin Willander, Roza Chaireti
1Department of Medical and Health Sciences, Linköping University, Linköping, Sweden.
Background:
TP53 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 Design:
We 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) ).
Results:
We found a high frequency (22%) of TP53mut in patients with cytogenetic aberrations, with association to high-risk cytogenetics (P < 0.001). TP53mut patients had lower response rates (22% compared with 76% CR in TP53 wild-type (wt) patients, P < 0.001) and reduced OS (2 and 16 months, respectively, P < 0.001). 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. 50 months, P = 0.020).
Conclusions:
Our 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.
Insights
TP53 mutations and MDM2 SNP309 impact acute myeloid leukemia outcomes. TP53 mutations are linked to poor prognosis, while MDM2 SNP309 affects survival in specific patient groups.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- TP53 mutations are common in cancers, leading to treatment resistance and poor prognosis.
- Altered mouse double minute 2 (MDM2) expression can attenuate p53 signaling, promoting tumor growth and apoptosis resistance.
- The MDM2 SNP309 polymorphism may increase MDM2 expression, impairing normal p53 function.
Purpose of the Study:
- To investigate the frequency and prognostic impact of TP53 mutations (TP53mut) and MDM2 SNP309.
- To assess their effect on treatment outcomes and overall survival (OS) in acute myeloid leukemia (AML).
Main Methods:
- Analysis of 189 Swedish AML patients.
- TP53 mutations (exons 5-8) detected via single-strand conformation assay (SSCA) and direct sequencing.
- MDM2 SNP309 genotyped using Pyrosequencing.
Main Results:
- TP53 mutations occurred in 22% of patients with cytogenetic aberrations, associated with high-risk cytogenetics (P < 0.001).
- TP53mut patients showed lower response rates (22% vs. 76% CR) and reduced OS (2 vs. 16 months) compared to TP53 wild-type (wt) (P < 0.001).
- In TP53wt patients with intermediate/high-risk aberrations, MDM2 SNP309 G-allele carriers had shorter OS (median 9 vs. 50 months, P=0.020).
Conclusions:
- TP53 mutation analysis and MDM2 SNP309 genotyping are valuable for prognostication and risk stratification in AML.
- These genetic markers can aid in selecting patients for targeted therapies.
- The findings highlight the role of p53 pathway alterations in AML treatment response and survival.
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