Mutational analysis of therapy-related myelodysplastic syndromes and acute myelogenous leukemia

Abstract

Therapy-related myelodysplastic syndromes and acute myelogenous leukemia comprise a poor-risk subset of myelodysplastic syndromes and acute myelogenous leukemia. Large-scale mutation profiling efforts in de novo myelodysplastic syndromes have identified mutations that correlate with clinical features, but such mutations have not been investigated in therapy-related myelodysplastic syndromes and acute myelogenous leukemia. Genomic DNA from 38 patient samples were subjected to high throughput polymerase chain reaction and sequenced for TP53, TET2, DNMT3A, ASXL1, IDH1, IDH2, EZH2, EED, SUZ12, RBBP4, SRSF2, U2AF35, and SF3B1. We identified somatic mutations in 16 of 38 (42%) patients. TP53 mutations were the most common lesion, detected in 8 of 38 (21%) patients, followed by TET2 in 4 of 38 (10.5%). Cases with a TP53 mutation or loss of the TP53 locus had a worse overall survival compared to those with wild-type TP53 (8.8 vs. 37.4 months; P=0.0035).

Figure 1.

Somatic point mutations and cytogenetic abnormalities in tMDS/AML patients. Each column represents 1 patient. Gray, present or received (treatment agent or modality). X, unavailable data. 17p loss detected by karyotype or FISH. #11q23 rearrangement or amplification. *AML sample. For “Sample type”: gray, BM sample; white, peripheral blood. For “Blast percentage”: black, greater than or equal to 20%; gray, between 5% and 20%; white, less than 5% (in sample at time of collection).

Figure 2.

Survival of t-MDS/AML patients worsens with TP53 alterations. Median Survival of TP53 mutant/17p loss patients 8.8 months vs. TP53 wild type 37.4 months. (P=0.0035) by log-rank (Mantel-Cox) test. Table below graph, number of patients at risk at designated time points.