Abstract
BackgroundBCOR (BCL6 corepressor) is an epigenetic regulator gene involved in the specification of cell differentiation and body structure development. Recurrent somatic BCOR mutations have been identified in myelodysplastic syndrome (MDS). However, the clinical impact of BCOR mutations on MDS prognosis is controversial and the response of hypomethylating agents in MDS with BCOR mutations (BCORMUT) remains unknown.ResultsAmong 676 MDS patients, 43 patients (6.4%) harbored BCOR mutations. A higher frequency of BCOR mutations (8.7%) was investigated in patients with normal chromosome, compared to 4.2% in patients with abnormal karyotype (p = 0.040). Compared to the BCORWT patients, the BCORMUT patients showed a higher ratio of refractory anemia with excess blasts subset (p = 0.008). The most common comutations with BCOR genes were ASXL1 (p = 0.002), DNMT3A (p = 0.114) and TET2 (p = 0.148). When the hierarchy of somatic mutations was analyzed, BCOR mutations were below the known initial mutations (ASXL1 or TET2) but were above U2AF1 mutations. Transformation-free survival was significantly shorter in BCORMUT patients than that in BCORWT patients (16 vs. 35 months; p = 0.035). RNA-sequencing was performed in bone marrow mononuclear cells from BCORMUT and BCORWT patients and revealed 2030 upregulated and 772 downregulated genes. Importantly, HOXA6, HOXB7, and HOXB9 were significantly over-expressed in BCORMUT patients, compared to BCORWT patients. Eight of 14 BCORMUT patients (57.1%) achieved complete remission (CR) with decitabine treatment, which was much higher than that in BCORWT patients (28.7%, p = 0.036). Paired sequencing results (before and after decitabine) showed three of 6 CR patients lost the mutated BCOR. The median survival of CR patients with a BCORMUT was 40 months, which was significantly longer than that in patients with BCORWT (20 months, p = 0.036). Notably, prolonged survival was observed in three BCORMUT CR patients even without any subsequent therapies.ConclusionsBCOR mutations occur more frequently in CN MDS patients, predicting higher risk of leukemia transformation. BCORMUT patients showed a better response to decitabine and achieved longer post-CR survival.
Highlights
BCOR (BCL6 corepressor) is an epigenetic regulator gene involved in the specification of cell differen‐ tiation and body structure development
Six of the 43 patients presented isolated BCOR mutations, and all the remaining BCOR mutations coexisted with mutations in other genes, most significantly including ASXL1 (13/43 BCORMUT patients, 30.2%, vs. 84/633 B CORWT patients, 13.3%; p = 0.002), DNMT3A (8/43 BCORMUT patients, 18.6%, vs. 68/633 BCORWT patients, 10.7%; p = 0.114), and TET2 (10/43 BCORMUT patients, 23.3%, vs. 95/633 B CORWT patients, 15.0%; p = 0.148)
Mutation of RUNX1 (reported by Frederik Damm [7] to be the most common comutation was inconspicuous in this assay (7/43 BCORMUT patients, 16.3%, vs. 95/633 B CORWT patients, 15.0%; p = 0.822) (Fig. 1b)
Summary
BCOR (BCL6 corepressor) is an epigenetic regulator gene involved in the specification of cell differen‐ tiation and body structure development. Recurrent somatic BCOR mutations have been identified in myelodysplastic syndrome (MDS). The myelodysplastic syndrome (MDS) is an epigenetic disease characterized by increased stem cell proliferation coupled with aberrant differentiation resulting in a. Cellular differentiation is an epigenetic process that requires specific and highly ordered DNA methylation and histone modification programs. Aberrant differentiation in MDS can often be traced to abnormal DNA methylation as well as mutations in genes that regulate epigenetic programs involved in DNA methylation or histone modification control [1]. The BCL6 corepressor (BCOR) is located on chromosome X, in the Xp11.4 locus, taking part in a specific type of polycomb repressive complex (PRC) 1.1 that mediates transcriptional repression through epigenetic modifications of histones. Constitutional inactivating mutations of this gene have been implicated in many solid tumors and hematopoietic malignancies, including leukemia and MDS (perturbing myeloid differentiation and promoting leukemogenesis) [2, 3]
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