We read with interest the recent report demonstrating a high rate of prognostic p53 mutations in myelodysplastic syndrome (MDS) and secondary acute myeloid leukemia (AML) patients at Moffitt cancer center. 1 The investigators reported that p53 mutations were seen in 21% of their patients and were associated with complex karyotypes and reduced overall survival. Furthermore, they demonstrated that a p53 variant allele frequency (VAF) of more than 40% was associated with adverse prognosis when compared with VAF below 20%. 1 Other studies have also shown that p53 mutations are highly prognostic for adverse survival, though they have noticed a lower frequency of overall mutations in MDS. 2–8 We hypothesized that these outcomes were influenced by the populations examined and thus wanted to evaluate the prognostic significance of low allele burden mutations as well as determine the mutational landscape in a minority rich inner city cohort. We performed targeted sequencing at 500× coverage (Genoptix, Carlsbad, CA, USA) for 81 consecutive cases seen in a single institution in the Bronx and report that 60/81 (74%) patients were found to have at least one mutation of known significance. Mutational analysis revealed that TET2, p53, ASXL1 and DNMT3A were the most recurrently mutated genes (> 10%) in MDS/AML. p53 mutations were seen at a higher frequency than observed in previous cohorts (1–6) and occurred in 14/81 (17%) patients (Supplementary Tables S1 and S2). 10/55 (18%) patients with MDS or MDS/myeloproliferative neoplasm overlap and 4/26 (15%) patients with AML had a p53 mutation with known significance. Only 2/10 MDS patients and 1/4 AML patients with p53 mutations were exposed to prior chemotherapy (Supplementary Table S2). p53 mutations were significantly associated with higher risk cytogenetics (Correl= 0.55 (0.38–0.69, P-value= 1.02× 10− 7), but not to any other demographic variables or disease subtypes. Mutations in TET2, ASXL1, DNMT3A and splicing factor mutations were seen at frequencies similar to previous studies.(Figure 1a, Supplementary Table S1). 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 (o20% 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 …