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.

Keywords: AML; Karyotype; MDS; Next generation sequencing; TP53; Therapy-related.

Figure 1

Mutational profiles in myeloid neoplasms. 1A. mutational profile of therapy-related myelodysplastic syndromes (t-MDS) versus de novo MDS. 1B. mutational profile of therapy-related acute myeloid leukemia (t-AML) versus de novo AML. Asterisk denotes genes with significant difference between therapy-related versus de novo MDS/AML.

Figure 2

Difference of mutational pattern between t-MDS/AML and de novo MDS/AML. 2A. Mutational pattern of t-MDS/AML in Circos plot. 2B. Mutational pattern of de novo MDS/AML in Circos plot. The thickness of connecting lines between two genes is proportional of the number of such cases. Areas without connecting lines denote cases with single gene mutation.

Figure 3

Percentages of mutations in cases with a normal karyotype, an abnormal non-complex karyotype and a complex karyotype, in different disease subtypes. TP53 denotes mutations in TP53 gene, and non-TP53 denotes mutations other than TP53 gene.