Journal
BLOOD
Volume 129, Issue 17, Pages 2347-2358Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2016-12-754796
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Funding
- Japan Society for the Promotion of Science [23249052, 22134006, 21790907, 26115009, 16H05338]
- Tailor-made Medical Treatment Program from Japan Agency for Medical Research and Development [15km0305018h0101]
- Project for Cancer Research and Therapeutics Evolution (P-CREATE) from Japan Agency for Medical Research and Development [16cm0106501h0001, 16cm0106422h0001]
- Foundation for the National Institutes of Health (Bethesda, MD) (National Heart, Lung, and Blood Institute) [Cleveland, OH] [RO1HL-082983, K24 HL-077522]
- Foundation for the National Institutes of Health (Bethesda, MD) (National Institute of General Medical Sciences) [Cleveland, OH] [U54 RR019391]
- Scott Hamilton CARES grant (Cleveland, OH)
- Edward P. Evans Foundation (Cleveland, OH)
- Grants-in-Aid for Scientific Research [15H05912, 16H05338, 26115009, 15J02911, 17K16189, 17H04209, 15H05909, 26221308] Funding Source: KAKEN
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Genetic alterations, including mutations and copy-number alterations, are central to the pathogenesis of myelodysplastic syndromes and related diseases (myelodysplasia), but their roles in allogeneic stem cell transplantation have not fully been studied in a large cohort of patients. We enrolled 797 patients who had been diagnosed with myelodysplasia at initial presentation and received transplantation via the Japan Marrow Donor Program. Targeted-capture sequencing was performed to identify mutations in 69 genes, together with copy-number alterations, whose effects on transplantation outcomes were investigated. We identified 1776 mutations and 927 abnormal copy segments among 617 patients (77.4%). In multivariate modeling using Cox proportional-hazards regression, genetic factors explained 30% of the total hazards for overall survival; clinical characteristics accounted for 70% of risk. TP53 and RAS-pathway mutations, together with complex karyotype (CK) as detected by conventional cytogenetics and/or sequencing-based analysis, negatively affected posttransplant survival independently of clinical factors. Regardless of disease subtype, TP53-mutated patients with CK were characterized by unique genetic features and associated with an extremely poor survival with frequent early relapse, whereas outcomes were substantially better in TP53-mutated patients without CK. By contrast, the effects of RAS-pathway mutations depended on disease subtype and were confined to myelodysplastic/myeloproliferative neoplasms (MDS/MPNs). Our results suggest that TP53 and RAS-pathway mutations predicted a dismal prognosis, when associated with CK and MDS/MPNs, respectively. However, for patients with mutated TP53 or CK alone, long-term survival could be obtained with transplantation. Clinical sequencing provides vital information for accurate prognostication in transplantation. Clinical sequencing provides vital information for accurate prognostication in transplantation.
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