<i>U2AF1</i> mutation variants in myelodysplastic syndromes and their clinical correlates

Tefferi, Ayalew; Mudireddy, Mythri; Finke, Christy; Nicolosi, Maura; Lasho, Terra L.; Hanson, Curtis A.; Patnaik, Mrinal M.; Pardanani, Animesh; Gangat, Naseema

doi:10.1002/ajh.25084

Cited by 17 publications

(32 citation statements)

References 12 publications

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“…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…”

Section: Data Extractionmentioning

confidence: 99%

“…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).…”

Section: Outcome Of the Meta-analysismentioning

confidence: 99%

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

Zou

Yang

et al. 2019

J Int Med Res

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Introduction: Although the effects of U2 small nuclear RNA auxiliary factor 1 gene (U2AF1) mutations on the outcomes of patients with myelodysplastic syndromes (MDS) have previously been investigated, their prognostic significance remains controversial. We performed a metaanalysis to investigate the impact of U2AF1 mutations on MDS progression. Methods: Two reviewers independently extracted information such as hazard ratios (HRs) and 95% confidential intervals (CIs) for overall survival (OS) and leukemia-free survival (LFS) as well as the number of surviving patients each year after diagnosis from the included studies. Results: Thirteen studies with a total of 3038 patients were included. The summary odds ratio (OR) for U2AF1 mutations with an OS of 5 years was 0.37, the summary HR for U2AF1 mutations in OS was 1.60, and the summary OR for an OS of 5 years in patients with U2AF1 S34 and U2AF1 Q157 was 3.68. There were no significant differences in leukemia-free survival or hypomethylating therapy response between patients with and without U2AF1 mutations. Conclusion: U2AF1 mutations were associated with poor survival in MDS patients, and patients with U2AF1 Q157 had a worse OS than those with U2AF1 S34 . Our findings suggest that MDS patients with U2AF1 mutations could benefit more from hypomethylation therapy.

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Section: Data Extractionmentioning

confidence: 99%

Section: Outcome Of the Meta-analysismentioning

confidence: 99%

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

Zou

Yang

et al. 2019

J Int Med Res

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“…Studies show that U2AF1 mutation sites may affect the prognosis. Q157 site mutation has worse prognosis than S34 mutation 14 , 16 , 17 . Gradual accumulation of mutant genes can promote the occurrence and progress of MDS.…”

Section: Introductionmentioning

confidence: 96%

Differential U2AF1 mutation sites, burden and co-mutation genes can predict prognosis in patients with myelodysplastic syndrome

Wang

Guo

Dong

et al. 2020

Sci Rep

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To investigate the U2AF1 gene mutation site, mutation load and co-mutations genes in patients with myelodysplastic syndrome (MDS) and their effects on prognosis. Gene mutation detection by next-generation sequence and related clinical data of 234 MDS patients were retrospectively collected and analyzed for the relationship between the clinical characteristics, treatment efficacy and prognosis of U2AF1 gene mutation. Among the 234 MDS patients, the U2AF1 gene mutation rate was 21.7% (51 cases), and the median variant allele frequency was 39.5%. Compared with the wild type, the U2AF1 mutant had a higher incidence of chromosome 8 aberration, and was positively correlated with the occurrence of ASXL1, RUNX1, SETBP1 gene mutation, negatively correlated with SF3B1, NPM1 genes mutation (p < 0.05). The most common mutation site of U2AF1 was S34F (32 cases), while U2AF1 Q157P site mutations had a higher incidence of chromosome 7 abnormalities (p = 0.003). The U2AF1 gene mutation more frequently coincided with signal pathway related gene mutations (p = 0.043) with a trend of shortened overall survival. Among patients with U2AF1 gene mutations, those with ASXL1 mutations were prone to develop into acute myeloid leukemia, those with RUNX1 mutations had an increased risk of relapse, and those with TET2 mutations had higher 1-year survival rate. Compared with the patient group of lower mutation load (VAF ≤ 40%), the group with higher mutation load of U2AF1 (VAF > 40%) had a significantly lower 1-year survival rate (46.1% and 80.5%, p = 0.027). The criteria of U2AF1 VAF > 40% is an independent indicator for poor prognosis of MDS patients. VAF > 40% of U2AF1 is an independent factor of short OS in MDS patients. MDS patients with a mutation in the Q157P site of U2AF1 and a higher U2AF1 mutation load suggests poor prognosis, and co-mutated genes in U2AF1 can affect disease progression and prognosis.

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“…Investigation of MDS at the molecular level has increased our understanding of recurrently mutated pathways including those of RNA splicing, DNA methylation, transcription regulation and chromatin and histone modification. Multiple studies have now demonstrated the significance of somatic point mutations in MDS, in regards to overall and leukemic free survival . Accordingly, we and others have already started incorporating genetic information into clinical risk models in MDS .…”

Section: Discussionmentioning

confidence: 99%

“…The revised international prognostic scoring system (IPSS‐R) is currently the standard tool used to risk stratify MDS patients and is based on both clinical and cytogenetic data . Most recently, next‐generation sequencing (NGS) technology has enabled identification of mutations in MDS that adversely affect overall or leukemia‐free survival, including ASXL1 , TP53 , EZH2 , ETV6 , RUNX1 , WT1 , SRSF2 , IDH1 , IDH2 , DNMT3A , SETBP1 , CSF3R , and others . Several teams of investigators have now begun incorporating mutation information into clinical risk models; the most noteworthy in this regard was the Mayo Alliance prognostic model for MDS; in the particular study that included 685 molecularly‐annotated patients from the Mayo Clinic and the National Taiwan University Hospital, multivariable analysis identified monosomal karyotype (MK), “non‐MK abnormalities other than single/double del(5q),” RUNX1 and ASXL1 mutations, absence of SF3B1 mutations, age > 70 years, hemoglobin <8 g/dL in women or <9 g/dL in men, platelet count <75 × 10 9 /l and bone marrow blasts ≥10%, as predictors of inferior overall survival; subsequently, a four‐tiered risk model was devised, with median survivals of 85 months for low, 42 months for intermediate‐1, 22 months for intermediate‐2 and 9 months for high risk disease.…”

Section: Introductionmentioning

confidence: 99%

Mutations and karyotype predict treatment response in myelodysplastic syndromes

et al. 2018

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We examined the influence of mutations and karyotype on conventional treatment response, specifically hematological improvement in anemia, in primary myelodysplastic syndromes (MDS). Cytogenetic and next generation sequencing (NGS)-derived mutation information was available in 357 patients (median age 74 years; 70% males); the revised international prognostic scoring system risk distribution was very high in 11%, high 15%, intermediate 17%, low 40% and very low 16%. At least one mutation was detected in 81% of patients; most frequent were SF3B1 (32%), ASXL1 (27%), TET2 (24%) and U2AF1 (15%). At median follow-up of 24 months, treatment with hypomethylating agents (HMAs) was documented in 121 (34%) patients, lenalidomide (LEN) in 55 (15%), and erythropoiesis stimulating agents (ESAs) in 136 (38%). ASXL1 mutations adversely affected response to HMAs (27% vs 48%; P = 0.02) and LEN (9% vs 43%; P = 0.04), but not ESAs (P = 0.6). LEN response was also adversely affected by U2AF1 mutations (0% vs 42%; P = 0.02) and high risk karyotype (0% vs 41% in intermediate vs 47% in low risk; P = 0.01). Patients with SF3B1 mutations were more likely to respond to LEN (56% vs 27%; P = 0.04). Contrary to previous reports, we found no association between TET2 mutations and HMA treatment response (40% vs 41%; P = 0.9), even in the absence of ASXL1 mutations (P = 0.4).We conclude that ASXL1 mutations in MDS predict inferior response to treatment with both HMAs and LEN; response to LEN was also compromised by U2AF1 mutations and high risk karyotype; SF3B1 mutations identified patients likely to respond to LEN.

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U2AF1 mutation variants in myelodysplastic syndromes and their clinical correlates

Cited by 17 publications

References 12 publications

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

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

Differential U2AF1 mutation sites, burden and co-mutation genes can predict prognosis in patients with myelodysplastic syndrome

Mutations and karyotype predict treatment response in myelodysplastic syndromes

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