Clinical features and biological implications of different U2AF1 mutation types in myelodysplastic syndromes

Abstract

U2AF1 mutations (U2AF1MT) occur commonly in myelodysplastic syndromes (MDS) without ring sideroblasts. The aim of this study was to investigate the clinical and biological implications of different U2AF1 mutation types in MDS. We performed targeted gene sequencing in a cohort of 511 MDS patients. Eighty-six patients (17%) were found to have U2AF1MT, which occurred more common in younger patients (P = .001) and represented ancestral lesions in a substantial proportion (71%) of cases. ASXL1MT and isolated +8 were significantly enriched in U2AF1MT-positive cases, whereas TP53MT, SF3B1MT, and complex karyotypes were inversely associated with U2AF1MT. U2AF subjects were enriched for isolated +8 and were inversely associated with complex karyotypes. U2AF1MT was significantly associated with anemia, thrombocytopenia, and poor survival in both lower-risk and higher-risk MDS. U2AF1 subjects had more frequently platelet levels of <50 × 10 /L (P = .043) and U2AF1 /U2AF1 subjects had more frequently hemoglobin concentrations at <80 g/L (P = .008) and more often overt fibrosis (P = .049). In conclusion, our study indicates that U2AF1MT is one of the earliest genetic events in MDS patients and that different types of U2AF1MT have distinct clinical and biological characteristics.

Prognostic significance of U2AF1 mutations in myelodysplastic syndromes: a meta-analysis

“…HRs and 95% CIs for OS and LFS were also extracted from the included studies together with the number of patients which survived every year after diagnosis. If the article provided 19 Wu, 2016 20 Jung, 2016 17 Hwang, 2016 16 Kang, 2015 18 Hong, 2015 15 Kim, 2017 13 Tefferi, 2018 21 Hamilton, 2019 22 Xu, 2017 26 Tefferi, 2017 24 Heuser, 2017 23 Wu, 2013 25 Journal Genes Chromosomes…”

“…Abnormal karyotypes were encountered significantly more often in patients with than without U2AF1 mutations (49.6% vs. 37.8%, P < 0.05); similarly, patients with abnormal karyotypes were significantly more likely to have U2AF1 mutations (19.3% vs 12.1%, P < 0.05) ( Figure 2). As shown in Figure 3a-d, we analyzed the ORs of OS in MDS patients with U2AF1 mutations in eight studies; 13,[15][16][17][18][19][20][21] summary ORs for OS of 1, 2, 3, and 5 years were 0.76 (95% CI: 0.54-1.09), 0.47 (95% CI: 0.35-0.62, P < 0.001), 0.43 (95% CI: 0.24-0.78, P ¼ 0.006), and 0.37 (95% CI: 0.26-0.51, P < 0.001), respectively. In the case of 3-year OS, high heterogeneity was observed with an I 2 of 64% (P ¼ 0.006).…”

“…Some studies showed that U2AF1 mutations had no impact on the outcomes of MDS patients, 13,15,16 while others revealed them to be negative factors in MDS prognosis. [17][18][19][20] Hypomethylating agents such as azacytidine and decitabine have been shown by randomized phase III trials to decrease the risk of leukemic transformation and, in a portion of patients, to improve survival. 7 Thus, hypomethylating therapy (HTM) is considered a conventional treatment for MDS patients, and U2AF1 mutations have been reported to affect the response to HTM.…”

U2AF1 mutation variants in myelodysplastic syndromes and their clinical correlates

“…Additional studies are required to clarify the discrepant observation from another MDS study, where thrombocytopenia was specifically associated with U2AF1 S34 and anemia with U2AF1 Q157 mutation types. 11 Iron isomaltoside is superior to iron sucrose in increasing hemoglobin in gynecological patients with iron deficiency anemia To the Editor:…”

Characteristics of myeloproliferative neoplasms in patients exposed to ionizing radiation following the Chernobyl nuclear accident

“…These were missense U2AF1 p.Q157P (c.470A>C) with 23% allele frequency and nonsense DNMT3A p.C368X (c.C1104A) mutations with 21% allele frequency. U2AF1 p.Q157P (c.470A>C) was previously reported in patients with MDS 54,55 and PMF 56 . Interestingly, a daughter of this woman was diagnosed with acute leukemia.…”