Mutational profiling of therapy-related myelodysplastic syndromes and acute myeloid leukemia by next generation sequencing, a comparison with de novo diseases

Abstract

In this study we used a next generation sequencing-based approach to profile gene mutations in therapy-related myelodysplastic syndromes (t-MDS) and acute myeloid leukemia (t-AML); and compared these findings with de novo MDS/AML. Consecutive bone marrow samples of 498 patients, including 70 therapy-related (28 MDS and 42 AML) and 428 de novo (147 MDS and 281 AML) were analyzed using a modified-TruSeq Amplicon Cancer Panel (Illumina) covering mutation hotspots of 53 genes. Overall, mutation(s) were detected in 58.6% of t-MDS/AML and 56.8% of de novo MDS/AML. Of therapy-related cases, mutations were detected in 71.4% of t-AML versus 39.3% t-MDS (p=0.0127). TP53 was the most common mutated gene in t-MDS (35.7%) as well as t-AML (33.3%), significantly higher than de novo MDS (17.7%) (p=0.0410) and de novo AML (12.8%) (p=0.0020). t-AML showed more frequent PTPN11 but less NPM1 and FLT3 mutations than de novo AML. In summary, t-MDS/AML shows a mutation profile different from their de novo counterparts. TP53 mutations are highly and similarly prevalent in t-MDS and t-AML but mutations in genes other than TP53 were more frequent in t-AML than t-MDS. The molecular genetic profiling further expands our understanding in this group of clinically aggressive yet heterogeneous myeloid neoplasms.

Molecular characterization of acute erythroid leukemia (M6-AML) using targeted next-generation sequencing

“…As already observed, 5,6 we found a low frequency of FLT3 mutations, as compared with overall AML. The high frequency of TP53 mutations was similar to that found in t-AML 12 and AML with myelodysplastic related changes (MRC). 7 However, M6 samples had a lower frequency of ASXL1 mutations, considered as a marker of dysplasia, than AML-MRC.…”

Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel

“…[245][246][247][248] In a study analyzing mutation hotspots of 53 genes in 70 t-MNs (28 t-MDS, 42 t-AML), TP53 was the most commonly mutated gene in t-MDS (35.7%) and t-AML (33.3%). 248 Some individuals develop t-AML after treatment with topoisomerase II inhibitors; their latency period is often only 1 to 3 years, antecedent MDS is rare, and balanced rearrangements involving KMT2A (MLL) at 11q23, RUNX1 at 21q22, or PML/RARA are common. The distinction between these 2 subtypes has become less evident due to the use of multiagent chemotherapy, often in combination with radiotherapy.…”

More than 1 TP53 abnormality is a dominant characteristic of pure erythroid leukemia

“…Presence of preexisting TP53-mutant clones in patients receiving chemotherapy has been associated with development of therapy-related myeloid malignancies, 21 which are known to have higher frequency of these mutations. 22,23 Given the high frequency of therapy-related and secondary disease among these patients with PEL, it is possible that the high frequency of TP53 abnormalities is in part related to successive clonal selection of preexisting TP53-mutant clones. Importantly, few additional common AML mutations were identified, supporting the notion that multiple TP53 alterations represent a central biological hallmark in PEL development.…”