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Cytogenetics and molecular genetics

The mutational burden of therapy-related myeloid neoplasms is similar to primary myelodysplastic syndrome but has a distinctive distribution


Therapy-related myeloid neoplasms (T-MN) are poorly characterized secondary hematological malignancies following chemotherapy/radiotherapy exposure. We compared the clinical and mutational characteristics of T-MN (n = 129) and primary myelodysplastic syndrome (P-MDS, n = 108) patients. Although the somatic mutation frequency was similar between T-MN and P-MDS patients (93% in both groups), the pattern was distinct. TP53 mutations were more frequent in T-MN (29.5 vs. 7%), while spliceosomal complex mutations were more common in P-MDS (56.5 vs. 25.6%). In contrast to P-MDS, the ring sideroblasts (RS) phenotype was not associated with better survival in T-MN, most probably due to genetic association with TP53 mutations. SF3B1 was mutated in 96% of P-MDS with ≥15% RS, but in only 32% T-MN. TP53 mutations were detected in 92% T-MN with ≥15% RS and SF3B1 wild-type cases. Interestingly, T-MN and P-MDS patients with “Very low” or “Low” Revised International Prognostic Scoring System (IPSS-R) showed similar biological and clinical characteristics. In a Cox regression analysis, TP53 mutation was a poor prognostic factor in T-MN, independent of IPSS-R cytogenetics, disease-modifying therapy, and NRAS mutation. Our data have direct implications for T-MN management and provide evidence that, in addition to conventional disease parameters, mutational analysis should be incorporated in T-MN risk stratification.

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This work was supported by the Royal Adelaide Hospital Research Committee, Contributing Hematologists Committee, and Royal Adelaide Hospital.

Author contributions

DS: planned and performed mutational analysis, analyzed data, and wrote the manuscript. LYAW: processed samples, analyzed data, and edited the manuscript. MMK and RC: analyzed data and edited the manuscript. JG, AWS, JF, and PP-SW: analyzed bioinformatics data and provided critical comments. MB, WTP, and SH: processed samples and analyzed data. SE: provided statistical advice. SM and PA: analyzed data and provided critical comments. SB and ALB: provided critical comments and edited the manuscript. NS and RG: provided clinical information and critical comments. TK, LBT, PGB, IDL, RJD: provided critical comments. JPM: provided critical comments and edited the manuscript. HSS: developed the project, analyzed data, and edited the manuscript. CNH: developed the project, analyzed data, and edited the manuscript. DKH: developed the project, analyzed data, and edited the manuscript.

Author information

Conflict of interest

SB received research funding and honoraria and served on advisory committees from Novartis and Bristol-Myers Squibb, and consultancy fees and honoraria from Qiagen and Cepheid. HSS received honoraria from Celgene. The other authors declare that they have no conflict of interest.

Correspondence to Devendra K. Hiwase.

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