Patients with low-risk myelodysplastic syndromes (MDS) that rapidly progress to AML remain a challenge in disease management. Using whole-exome-sequencing of a MDS patient, we identified a somatic mutation in BCOR gene also mutated in AML. Sequencing of BCOR and related BCORL1 genes in a cohort of 354 MDS patients identified a total of 15 patients with inactivating BCOR mutations (15/354=4.2%) and 3 with BCORL1 mutations (3/354=0.8%). BCOR mutations were associated with RUNX1 (P=0.002) and DNMT3A mutations (P=0.015). Moreover, mutations of BCOR (4/54=7.4%) and BCORL1 (1/54=1.8%) were found in a cohort of 54 CMML, while BCORL1 mutations were found in 9.1% of 22 AML-MRC patients. Using deep sequencing, we show that BCOR mutations arise after mutations affecting genes involved in splicing machinery or epigenetic regulation. In univariate analysis, BCOR mutations were associated with poor prognosis in MDS (OS: P=0.013; cumulative incidence of AML transformation: P=0.005). Multivariate analysis including age, IPSS, transfusion dependence, ASXL1, CBL, RUNX1, TEL/ETV6, and TP53 mutation status confirmed a significant inferior OS to patients with BCOR mutation (HR: 3.3; 95%CI 1.4-8.1; P=0.008). These data suggest that BCOR mutations define the clinical course rather than disease initiation. Despite infrequent mutations, BCOR analyses should be considered in risk stratification.
- myelodysplastic syndromes (MDS)