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High prevalence and allele burden-independent prognostic importance of p53 mutations in an inner-city MDS/AML cohort

Leukemia volume 30, pages 1793–1795 (2016)Cite this article

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At the time of analysis, 44 (54%) patients were alive, 32 (40%) patients were dead and 5(6%) were lost to follow up. Commonest causes of death were disease progression (60%), infection (25%) and bleeding (13%). Analysis of overall survival in this cohort revealed that p53 and TET2 mutations were associated with a significant decrease in overall survival (Figure 1b, Supplementary Figure S1A). p53 mutational status was found to be the strongest predictor of adverse prognosis with median survival of 145 days in mutated cases versus 593 days in p53 wild–type (WT) cases (log-rank P-value=1.6 × 10−6) (Figure 1b). Time to progression to AML was also found to be significantly shorter in p53-mutated cases of MDS. 4/10 patients with p53-mutated MDS progressed to AML within a short period of time (median time to progression in p53 mutation was 272 days versus not reached in p53 WT cases, log-rank P-value=1.2 × 10−5, Figure 1c). The other 6/10 p53-mutated MDS patients died within less than 12 months of diagnosis due to infections and other disease-related morbidities. Other mutated genes were not linked with significant changes in overall survival (Supplementary Table S1).

Interestingly, we observed that low variant allele burdens of p53 mutation (<20% VAF) was seen in 7/14(50%) of patients. Comparison of low with high-variant allele burden patients revealed that a low VAF was equally associated with adverse prognosis (log-rank P-value=0.2) (Figure 1d). In fact, serial testing done in a patient with low p53 VAF revealed rapid increase in allele burden with standard therapy. The patient had MDS (RAEB) with a VAF of 16%; was started on Azacytidine and progressed to AML within a short duration (5 months) with accompanying increase in p53 allele burden to 65% VAF (Supplementary Figure S1B). To validate these findings we analyzed the association of p53 mutations with overall survival in a large independent cohort from Cleveland Clinic.9 A total of 36 p53 mutations were seen in this validation cohort and were found to be prognostic for adverse survival (Figure 1e, log-rank P-value =0.019). Consistent with our findings, in this cohort, survival of patients with low p53 VAF was not significantly different from patients with high VAF (Figure 1f).

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Authors and Affiliations

  1. Department of Oncology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, USA

    S Goel, K Pradhan, A Shastri, I Mantzaris, M Janakiram, R Battini, N Kornblum, O Derman, K Gritsman, B Halmos, U Steidl, I Braunschweig & A Verma

  2. Genoptix, Carlsbad, CA, USA

    J Hall & J Al-Hafidh

  3. Taussig Cancer Center, Cleveland Clinic, Cleveland, OH, USA

    C Hirsch, B Przychodzen & J P Maciejewski

  4. Department of Pathology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, USA

    Y Wang

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Correspondence to S Goel, J P Maciejewski, I Braunschweig or A Verma.

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Goel, S., Hall, J., Pradhan, K. et al. High prevalence and allele burden-independent prognostic importance of p53 mutations in an inner-city MDS/AML cohort. Leukemia 30, 1793–1795 (2016). https://doi.org/10.1038/leu.2016.74

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