BCOR and BCORL1 mutations in Myelodysplastic Syndromes (MDS): Clonal Architecture and Impact on Outcomes

Background

Several recurrent somatic mutations have been identified in MDS and these mutations play an important role in disease pathophysiology and outcome. BCOR and BCORL1 are located on chromosome X and interact with histone deacetylases and other cell functions. The BCOR gene is mutated (BCOR^MUT) in 4-6% of MDS patients (pts) and is associated with poor outcome. BCORL1 mutations (BCORL1^MUT ) are present in <1% of MDS pts with an unknown impact on OS. We investigated the clonal architecture of BCOR and BCORL1 in MDS and the impact of these mutations on clinical outcome.

Methods

We sequenced DNA samples from pts with MDS and related myeloid malignancies (MDS/myeloproliferative neoplasms (MPN) and secondary AML) for the presence of BCOR and BCORL1 mutations and 58 other genes that have been described as recurrently mutated in myeloid malignancies. The Revised International Prognostic Scoring System (IPSS-R) was calculated as descried previously. Overall survival (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 architecture of driver clones.

Results

Of 621 included MDS pts, 29 (5%) had BCOR mutations and 13 (2%) had BCORL1 mutations. Patients with BCOR mutations were younger (median age 63 vs. 68 years, p= .04), and had a lower platelet counts 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 were also similar for BCOR^MUTcompared toBCOR^WT:very low 10 vs. 16%, low 31 vs. 40%, intermediate 24 vs. 18%, high 17 vs. 14%, and very high 13 vs. 10%, respectively, 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%). 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). Clonal architecture analysis identified BCOR mutations as ancestral, subclonal, and mosaic in 41%, 21% and 38% of cases respectively. The median OS for BCOR^MUT pts was 24.5 months compared to 17.9 months for BCOR^WT, p = .23). The impact of BCOR mutations on OS was neutral even after adjustment for age and IPSS-R risk categories.

Pts with BCORL1^MUT had lower WBC counts (median 2.7 vs. 4 10⁹/L p = .02), and lower platelets counts at diagnosis (72 vs. 91 10⁹/L, p = .02) compared to BCORL1^WT pts. In cytogenetic analyses, BCORL1^MUT was associated with a higher incidence of very good cytogenetics per IPSS-R (15% vs. 2%, p =.001). Further, BCORL1^MUT were more likely to be classified in the intermediate risk group per IPSS-R (46 vs. 18%, p = .01) and less likely to be classified in the low risk group (7 vs. 40%, p = .01) compared to BCORL1^WT. BCORL1 mutations were missense in 7 patients (53%), frameshift insertion/deletion in 3 (23%), stopgain in 1 (7%), and nonsense in 2 (15%). BCORL1 is commonly co-mutated with TET2 (p =.001), BCOR (p <.001) DHX29 (p = .001), C7orf55 (p =.02), and FLT3 (p =.03). Clonal architecture analysis identified BCORL1 mutations as ancestral, subclonal, and mosaic in 61%, 23% and 15% of patients respectively. The median OS for BCORL1^MUTpts was longer compared to BCORL1^WT, but was not significantly different (43.8 vs. 19.9, respectively, p = .16) even after adjustment for age and IPSS-R risk categories.

Conclusion

BCOR and BCORL1 mutations occur with low frequency in MDS. These mutations can be ancestral or subclonal. The impact of BCOR mutations on OS was neutral even after adjustment for age and IPSS-R risk scores. Although the median OS for pts with BCORL1^MUT was longer compared to BCORL1^WT,it was not statistically significant. A larger pt population with BCOL1 may show a positive impact of these mutations on OS.