Additional myelodysplasia-related genes mutations affected the clinical presentations and prognosis of patients with SRSF2/TET2 co-mutations

Abstract Background Myeloid neoplasms (MN) display marked clinical and molecular heterogeneity. The 2022 WHO and ICC classifications prioritize genomic profiling, particularly myelodysplasia-related gene (MRG) mutations, including SRSF2, SF3B1, U2AF1, ZRSR2, ASXL1, EZH2, BCOR, and STAG2, now recognized as key diagnostic and prognostic molecular markers in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). SRSF2 and TET2 are two driver mutations frequently seen together in MDS, and myelodysplastic/myeloproliferative neoplasm (MDS/MPN), especially in chronic myelomonocytic leukemia (CMML). In this study, we examined the clinical and prognostic impact of additional mutated MRGs (SF3B1, U2AF1, ZRSR2, ASXL1, EZH2, BCOR, and STAG2) in patients with SRSF2/TET2 co-mutations. Methods A cohort of 412 patients with co-mutations in SRSF2 and TET2 was retrospectively identified from the Moffit Next-Generation Sequencing (NGS) database. Demographic, pathologic, cytogenetic, and FISH data were collected under IRB approval. Cytogenetic risk was assigned using NCCN and Spanish CMML-specific guidelines. The primary endpoint was overall survival (OS), defined as time of first NGS test to death or last contact. The prognostic impact of MRG mutations was assessed using Kaplan-Meier and Log Rank tests. Results Patient demographics and Cytogenetics Among 412 patients with SRSF2/TET2 co-mutations, more than half (227 patients, 55%) had at least one additional MRG mutation. There were 183 (44.4%) patients with a mutation in ASXL1, 20 (4.9%) in BCOR, 15 (3.6%) in EZH2, 12 (2.9%) in SF3B1, 37 (9.0%) in STAG2, 3 (0.7%) in U2AF1, and 17 (4.1%) in ZRSR2. These patients showed no significant differences in age or gender. Interestingly, patients with additional MRG mutations were significantly less likely to present with 5q deletion (1.1% vs 5.2%, p = .039) and 20q deletion (2.2% vs 8.8%, p = 0.007). CBC and Bone marrow findings Patients with additional MRG mutations had significantly lower hemoglobin (9.67 ± 2.03 vs 10.69 ± 2.38, p = .001) and bone marrow blasts (13.34 ± 19.19 vs 14.73 ± 24.89, p = .028) though there was no significant difference in bone marrow cellularity. Monocyte count was significantly higher among patients with additional MRG mutations (2.27 ± 5.46 vs 2.24 ± 3.93, p = .008). There were no statistically significant differences in WBC, platelet count, or peripheral blood (Pb) blasts. Diagnoses Patients with AML in this group were significantly more likely to have mutations in BCOR (9.2% vs 2.6%, p = .003), STAG2 (13.4% vs 6.7%, p = .023), and ZRSR2 (7% vs 2.6%, p =.031). Patients with additional MRG mutations were significantly more likely to be diagnosed as AML from CMML (12.3% vs 5.9%, p = .029) than CMML (31.7% vs 53.5%, p = .001). Patients with additional MRG mutations were also more likely to be diagnosed with MDS (16.3% vs 8.1%, p = .016). Overall Survival The median survival was significantly lower among patients with additional MRG mutations (95% CI, 10.941, 9.140 - 12.741), compared to patients without (23.787, 16.925 - 30.649, p .001). The median survival was also lower in patients with an ASXL1 mutation (95% CI, 11.532, 9.886 - 13.179), compared with patients without (19.023, 13.430 - 24.616, p = .024). None of the other MRG mutations individually had a statistically significant impact on survival, likely due to small sample sizes. Not surprisingly, the patients diagnosed with AML had approximately a 180% higher hazard rate of mortality compared to other diagnoses (95% CI, 2.777, 2.125 - 3.629, p .001). In patients with non-AML diagnosis, those with additional MRG mutations showed significantly lower OS (95% CI, 0.5749, 0.3999 - 0.8264) than the patients without (95% CI, 1.7395, 1.2101 - 2.5005, p = 0.0028). There is no significant difference in survival among AML patients. Conclusions Our results showed that additional MRG mutations affect the clinical presentation and prognosis of patients with SRSF2/TET2 mutations. Additional MRG mutations are common and are associated with monocytosis, anemia, and poorer survival, particularly in MDS patients. Despite comparable demographics and cytogenetics across groups, the presence of additional ASXL1 mutations independently predict worse outcomes. In AML cases, additional mutations in BCOR, STAG2, and ZRSR2 are more frequently observed. These findings may be used in future clinical practices to provide better prognoses to patients with SRSF2/TET2 co-mutated neoplasms.