BCOR Mutations in Myelodysplastic Syndromes (MDS): Mutation Characteristics Impact Clinical Outcomes

Introduction

Several recurrent somatic mutations have been identified in myelodysplastic syndromes (MDS) and these mutations play an important role in disease pathophysiology and outcome. BCOR is an X chromosome gene that interacts with histone deacetylases and other cell functions. BCOR, a co-repressor of BCL6, has been described in 4-6% of MDS patients (pts) and was reported to have a negative impact on overall survival (OS).

In this study, we explored the impact of these mutations on outcome and whether mutation characteristics (location, type, passenger vs. driver) can influence the outcome.

Method

Bone marrow and peripheral blood samples from MDS pts (defined at our institution per WHO criteria) were sequenced for the presence of BCOR mutations and 60 other genes that have been described as recurrently mutated in myeloid malignancies. OS was measured from the time of diagnosis to time of death or last follow-up. Variant allele frequencies (VAFs) adjusted by zygosity were used to define clonal architecture of driver clones.

Results

Of 621 pts included in the final analysis, 29 (5%) had BCOR mutations (BCOR^MUT). Pts with BCOR mutations were younger (median age 63 vs. 68 years, p= .04) and had a lower platelet count at diagnosis (63 vs. 93 10⁹/L, p= .01) compared to BCOR^WT pts. Cytogenetic risk categories per IPSS-R for BCOR^MUT was similar to BCOR^WT: very good 3% vs. 2%, good 65% vs. 62%, intermediate 10% vs. 17%, poor 13% vs. 7% and very poor 6% vs. 9%, respectively (p= .62). Risk categories per IPSS-R for BCOR^MUT were also similar to BCOR^WT: 41% very low/low, 24% intermediate, and 30% high/very high and were similar to BCOR^WT (p = .69 ). BCOR mutations were missense in 9 pts (31%), frameshift insertion/deletion in 10 (34%), stopgain in 8 (28%), and nonsense in 2 (6%). Clonal architecture analysis identified BCOR mutations as ancestral, subclonal, and mosaic in 41%, 21% and 38% of cases respectively. BCOR is commonly co-mutated with ASXL1 (p=.008), RUNX1 (p= .0001), NF1 (p=.002), ETV6 (p=.026), BCORL1 (p=.0001), MECOM (p=.021), RAD21 (p=.021), and CEBPA (p= .0001). The median OS for BCOR^MUT pts was 24.5 months compared to 17.9 months for BCOR^WT (p = .23 ). BCOR mutations had no significant impact on OS even after adjustment for age and IPSS-R risk categories (p = .23). However, survival differ based on mutation characteristics. The median OS for pts with frameshift mutations was 10.9 months compared to 50.4 months for pts with other types of mutation (p= .03). The median OS for pts with mutations occurring in the binding domains was 10.6 months compared to 38.8 months for mutations outside of the binding domains (p= .01). There was no significant impact on OS based on the mutation order, ancestry, subclonality or mosaicism.

Conclusion

BCOR mutations occur in 5% of pts with MDS and overall are not associated with OS even after adjustment for age and IPSS-R risk score. However, some mutation characteristics such as mutation location in the gene or the type of mutation (frameshift) do impact OS. Incorporating mutations characteristics such as location, type, and clonal hierarchy can affect prognostic implications of genomic abnormalities.