Mutations in DEAD/H-box Helicase 11 Correlate with Increased Relapse Risk in Adults with Acute Myeloid Leukaemia with Normal Cytogenetics

Abstract People with acute myeloid leukaemia with normal cytogenetics (CN-AML) have diverse outcomes explained, in part, by different mutation topography. DEAD/H-box helicase 11 mutations are associated with the rare genetic disease Warsaw breakage syndrome with increasing evidence of a potential role in oncogenesis. We studied DNA samples from 423 consecutive newly-diagnosed adults with CN-AML by deep targeted regional sequencing (TRS). DDX11 mutations were detected in 29 subjects and were significantly associated with higher cumulative incidence of relapse (CIR) with a Hazard Ratio (HR) = 2.17 (95% Confidence Interval [CI], 1.28, 3.66; P = 0.004) and worse relapse-free survival (RFS; HR = 2.19; [1.29, 3.73]; P = 0.004) compared with subjects with wild-type DDX11 in multi-variable analyses. About two-thirds of the DDX11 mutations were putative germline mutations based on variant allele frequency (VAF) analyses. In 2 subjects we proved germline origin of the DDX11 mutation by analyses of oral mucosa DNA samples from family members. Sub-group analyses suggested germline DDX11 mutations were also significantly associated with higher CIR compared with wild-type DDX11. In conclusion, we show the adverse impact of DDX11 mutations on relapse in persons with CN-AML. The trial is registered at Clinicaltrials.gov (NCT01455272, NCT02185261) and in chictr.org (ChiCTR-OCH-10000940).