Domain-based analysis of <i>RUNX1</i>somatic mutations in myeloid neoplasms.
Authors: Dakshin Sitaram Padmanabhan, Jeff Justin Aguilar, Vikram Dhillon, Lakshmi Bhavani Potluri, Sushmitha Nanja Reddy, Sandhya Dhiman, Paul Kim, Julie Boerner, David Carr, Jay Yang, Jaroslaw P. Maciejewski, Suresh Kumar Balasubramanian
Journal: Journal of Clinical Oncology (2024)

6542 Background: RUNX1is a master regulator of hematopoiesis. ELN2022 risk stratification categorizes RUNX1 as an AML/MDS gene associated with poor prognosis. Functional domains in RUNX1are the Runt homology domain (RHD) and a transactivation domain (TAD), with DNA binding and co-activator recruitment functions, respectively. Domain-based analysis can elucidate the functional and biological impact of somatic RUNX1mutations, which have not yet been reported in the literature. Methods: Sequencing data from Karmanos Cancer Institute and a publicly available meta-analytic cohort [Awada et al., Blood 2021, Kewan et al., Nature Communications 2023, cBioPortal (Cerami et al., 2012) and AACR GENIE (v 13.1)] were used to construct a larger dataset of 16,565 patients with myeloid neoplasms. Baseline clinical and molecular characteristics were noted. The chi-square test was used to study various parameters described, and Kaplan-Meier curves were used to estimate survival. Results: RUNX1was mutated in 10.8% (1804/16,565) of patients. Median OS (mOS) for RUNX1 MT vs. RUNX1 WT was significantly worse at 16.4 vs 23.4 mos. (p &lt; 0.0001). 990 patients with somatic mutations were studied; germline variants were screened and excluded if VAF was between 40-60%. Among somatic RUNX1 MT patients, primary AML was the most frequent at 52.8%, followed by secondary AML-35.7% and MDS-9%. Most patients had mutations in the RHD (53.8%), followed by TAD (22%), and the remaining in non-RHD, non-TAD zones (NRNT). There was no statistically significant difference in OS by domain stratification; TAD had the numerically least mOS at 13.6 mos, RHD at 16.1 mos, and NRNT at 20.4 mos. The median age of patients was 70.9 (62-76) years, similar across domains. TAD patients were less likely to be male when compared to RHD (47% vs. 56%, p=0.04). No specific enrichment of disease type or abnormal karyotype was observed across domains. Co-mutational profiles across RHD and TAD domains among all diseases showed spliceosome co-signature enriched in RHD vs. TAD (59% vs. 46%, p=0.01). NPM1was noted to be inversely correlated with RUNX1 in general, with 1% and 3.5% in RHD and TAD. ASXL1was the most frequently distributed co-mutation in both groups, but not statistically different (41% vs. 33%, p=0.11). TAD patients with spliceosome co-mutation had worse mOS (11.4 mos) than those without spliceosome mutation (16.2 mos, p=0.02) or RHD patients with spliceosome co-mutation (16 mos, p=0.001). Missense mutations were strongly associated with RHD (55.3% vs. 7.9%); p &lt;0.00001, while frameshift mutations were enriched in TAD (24.1% vs. 69.8%); p&lt;0.0001. Conclusions: Domain-based analysis of somatic RUNX1 MT myeloid neoplasms reveals TAD mutation to be common in females, frequently a frameshift mutation, and numerically has the worst survival. There appears to be a unique spliceosome signature enrichment in RHD compared to TAD, with worse OS in TAD patients with spliceosome co-mutations overall.