Co-Mutation Landscape and Clinical Significance of RAS Pathway Related Gene Mutations in Patients with Myelodysplastic Syndrome

Abstract

Background Single gene mutations in the RAS pathway are uncommon and of unknown significance in myelodysplastic syndrome (MDS) patients, RAS pathway-related gene mutations (RASwaymut) as a whole may be significant and require further elucidation. Objective To explore the clinical characteristics and co-mutation landscape of MDS patients in the background of RASwaymut. Methods The clinical data of 370 MDS patients who were newly diagnosed between November 1, 2016 and August 31, 2020 in our hospital were collected and retrospectively reviewed. Next generation sequencing (NGS) method was used to detect a panel of 96 selected MDS-related gene mutations. Results RASwaymut was detected in 15.41% (57/370) of primary MDS patients. Male dominance (78.95%.vs 64.54%, P=0.03), higher median percentage of marrow blasts (2% vs 1%, P=0.00) and more higher risk patients according to revised international scoring system(IPSS-R) (80.70% .vs 59.11%, P=0.002) as well as higher acute myeloid leukemia (AML) transformation rate (35.09% .vs 14.38%, P=0.02) were observed in patients with RASwaymut when compared to those with wild type RAS pathway-related genes (RASwaywt). The most common co-mutated genes were ASXL1 (28.6%); TET2 (23.2%); U2AF1, RUNX1, TP53 (14.3%); DNMT3A (12.5%); ZRSR2 (10.7%); among which ASXL1 mutation rate were significantly higher than those with RASwaywt (P＜0.05). RASwaymut had no significant effect on response to disease-modifying regimens in MDS patients. However, Overall survivals (OS) of RASwaymut patients were significantly shorter than those with RASwaywt (16.05m .vs 92.3m, P=0.00), mainly in patients with blast cells less than 5% (P=0.002), normal karyotype (P=0.01) and lower IPSS-R risk (P=0.00). While multivariate prognostic analysis showed that RASwaymut lost its effect on OS, and just when it co-mutated with TET2 was an independent poor prognostic factor for all MDS patients (P=0.00, HR=4.77 with 95%CI: 2.4-9.51) and RASwaymut patients (P=0.02, HR 2.76, 95%CI 1.21-6.29). Conclusion RASwaymutwas associated with higher marrow blast cells and IPSS-R risk, higher incidence of leukemic transformation thus shorter OS in MDS patients, it could be viewed as a whole to predict poor prognosis. Co-mutation with TET2 may promote disease progression and was an independent poor prognostic factor in MDS patients.