BCOR and BCORL1 mutations in myelodysplastic syndromes and related disorders

Abstract

Key Points• Despite a low frequency of mutations, BCOR might be considered as a key gene in risk stratification. • Deep sequencing technologiesshow that BCOR mutations commonly arise after other concomitant mutations in MDS.Patients with low-risk myelodysplastic syndromes (MDS) that rapidly progress to acute myeloid leukemia (AML) remain a challenge in disease management. Using whole-exome sequencing of an MDS patient, we identified a somatic mutation in the BCOR gene also mutated in AML. Sequencing of BCOR and related BCORL1 genes in a cohort of 354 MDS patients identified 4.2% and 0.8% of mutations respectively. BCOR mutations were associated with RUNX1 (P 5 .002) and DNMT3A mutations (P 5 .015). BCOR is also mutated in chronic myelomonocytic leukemia patients (7.4%) and BCORL1 in AML patients with myelodysplasia-related changes (9.1%). 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 (overall survival [OS]: P 5 .013; cumulative incidence of AML transformation: P 5 .005). Multivariate analysis including age, International Prognostic Scoring System, transfusion dependency, and mutational status confirmed a significant inferior OS to patients with a BCOR mutation (hazard ratio, 3.3; 95% confidence interval, 1.4-8.1; P 5 .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. (Blood. 2013;122(18):3169-3177)

Clarifying the Impact of Polycomb Complex Component Disruption in Human Cancers

“…Inactivating BCORL1 mutations have also been identified in 5.8% patients with AML, 9.1% patients with AML with myelodysplasia-related changes (AML-MRC), 0.8% patients with MDS, and 1.9% patients with CMML (Table 1; refs. 21,25). The distribution and types of BCORL1 mutations were similar to those of BCOR mutations (Fig.…”

“…Remarkably, BCOR mutations have been associated with poor prognosis in patients with CN-AML and MDS (20,21). In male patients with AML, BCOR mutations disrupted the single gene allele, whereas in female patients with AML, the mutations selectively targeted the functional allele because the exclusive expression of mutated BCOR was detected by cDNA-based amplicon deep sequencing (20).…”

“…Therefore, BCOR may also act as a single-hit tumor-suppressor gene in females. Targeted deep resequencing analyses of other myeloid-associated mutations revealed that in patients with MDS, somatic BCOR mutations arise after mutations in genes involved in splicing machinery or epigenetic regulation (21). These somatic mutations were scattered throughout the BCOR coding sequence and included nonsense, frameshift, insertion/deletion, and consensus splice-site mutations ( Fig.…”

Myelodysplastic syndromes: Contemporary review and how we treat

“…Of note, studies have identified mutations in TP53, EZH2, ETV6, RUNX1, ASXL1, DNMT3A, IDH1/ 2, BCL-6, SRSF2, NRAS, CBL, and STAG2 as predictors of shortened >3 Abnormalities (7*/na Serine/arginine-rich splicing factor 2 (SRSF2) Involved in splice-site selection, spliceosome assembly and both constitutive and alternative splicing. survival [7,9,11,62,63]. In a particular study by Bejar et al mutations of EZH2, RUNX1, TP53, and ASXL1 were associated with inferior overall survival independent of the LR-MDAS [12].…”

Nongenetic stochastic expansion of JAK2V617F-homozygous subclones in polycythemia vera?

“…Of the variants in subclone A alone, 5 mutations (plus JAK2V617F) were validated by capillary sequencing (Figure 1E-F; supplemental Table 2). Of these genes, BCOR shows recurrent frameshift mutations in acute myeloid leukemia and myelodysplasias, 7 whereas the others are not recurrently mutated in hematological malignancies. 6 The hemizygous BCOR mutation was detected in the dominant subclone A but also in a subset of colonies from minor subclone B ( Figure 1E-F).…”