Most common driver genes in patients with MDS and MDS/MPN
| Biological pathways and genes . | Frequency, %* . | Timing of mutation acquisition† . | Relationship between mutant gene and clinical phenotype . | Prognostic or predictive relevance of mutant gene . |
|---|---|---|---|---|
| RNA splicing | ||||
| SF3B1 | 15-30% | More often a founding mutation | Strictly associated with ring sideroblasts phenotype (RARS, RARS-T) | Associated with good overall survival and low risk of leukemic evolution |
| SRSF2 | 10-20% | More often a founding mutation | Associated with RCMD or RAEB, co-mutated with TET2 in CMML | Associated with poor overall survival and high risk of leukemic evolution |
| U2AF1 | <10% | More often a founding mutation | Mainly associated with RCMD or RAEB | Associated with high risk of leukemic evolution |
| ZRSR2 | <10% | More often a founding mutation | Not defined | Not defined |
| DNA methylation | ||||
| TET2 | 20-30% | More often a founding mutation | Found in all MDS subtypes, high mutation frequency (50-60%) in CMML | No impact on overall survival, may predict response to hypomethylating agents |
| DNMT3A | ∼10% | More often a founding mutation | Found in all MDS subtypes, co-mutated with SF3B1 in RARS | Associated with unfavorable clinical outcome (negative prognostic relevance mitigated by SF3B1 co-mutation in RARS) |
| IDH1/IDH2 | ∼5% | More often a founding mutation | Associated with RCMD or RAEB | Associated with unfavorable clinical outcome |
| Chromatin modification | ||||
| ASXL1 | 15-20% | More often a subclonal mutation | Associated with RCMD or RAEB, high mutation frequency (40%) in CMML | Associated with unfavorable clinical outcome in all myeloid neoplasms (MDS, MDS/MPN, MPN) |
| EZH2 | ∼5% | More often a subclonal mutation | Associated with RCMD or RAEB | Associated with unfavorable clinical outcome in all myeloid neoplasms |
| Transcription | ||||
| RUNX1 | ∼10% | Typical subclonal mutation | Associated with RCMD or RAEB | Associated with unfavorable clinical outcome |
| BCOR | <5% | Typical subclonal mutation | Associated with RCMD or RAEB | Associated with unfavorable clinical outcome |
| DNA repair control | ||||
| TP53 | ∼5% | Typical subclonal mutation | Associated with advanced disease and complex karyotype, mutated in 20% of patients with MDS with del(5q) | Associated with poor overall survival and high risk of leukemic evolution, predicts poor response to lenalidomide in MDS with del(5q) |
| Cohesin | ||||
| STAG2 | <10% | More often a subclonal mutation | Associated with RCMD or RAEB. Mutated in about 10% of patients with AML | Associated with unfavorable clinical outcome |
| RAS pathway | ||||
| CBL | <5% | More often a subclonal mutation | Found in different MDS subtypes, associated with JMML in children | Not defined in MDS |
| NRAS/KRAS | <5% | More often a subclonal mutation | Found in different MDS subtypes, associated with JMML in children | Not defined in MDS |
| NF1 | <5% | More often a subclonal mutation | Found in different MDS subtypes, associated with JMML in children | Not defined in MDS |
| DNA replication | ||||
| SETBP1 | <5% | More often a subclonal mutation | Found in 25% of patients with aCML and in subsets of patients with advanced MDS or CMML | Associated with poor overall survival and high risk of leukemic evolution |
| Receptors | ||||
| CSF3R | <1% | Founding driver mutation in CNL | Strictly associated with CNL, found in a subset of patients with aCML | Mutation type may predict response to specific inhibitors |
| Biological pathways and genes . | Frequency, %* . | Timing of mutation acquisition† . | Relationship between mutant gene and clinical phenotype . | Prognostic or predictive relevance of mutant gene . |
|---|---|---|---|---|
| RNA splicing | ||||
| SF3B1 | 15-30% | More often a founding mutation | Strictly associated with ring sideroblasts phenotype (RARS, RARS-T) | Associated with good overall survival and low risk of leukemic evolution |
| SRSF2 | 10-20% | More often a founding mutation | Associated with RCMD or RAEB, co-mutated with TET2 in CMML | Associated with poor overall survival and high risk of leukemic evolution |
| U2AF1 | <10% | More often a founding mutation | Mainly associated with RCMD or RAEB | Associated with high risk of leukemic evolution |
| ZRSR2 | <10% | More often a founding mutation | Not defined | Not defined |
| DNA methylation | ||||
| TET2 | 20-30% | More often a founding mutation | Found in all MDS subtypes, high mutation frequency (50-60%) in CMML | No impact on overall survival, may predict response to hypomethylating agents |
| DNMT3A | ∼10% | More often a founding mutation | Found in all MDS subtypes, co-mutated with SF3B1 in RARS | Associated with unfavorable clinical outcome (negative prognostic relevance mitigated by SF3B1 co-mutation in RARS) |
| IDH1/IDH2 | ∼5% | More often a founding mutation | Associated with RCMD or RAEB | Associated with unfavorable clinical outcome |
| Chromatin modification | ||||
| ASXL1 | 15-20% | More often a subclonal mutation | Associated with RCMD or RAEB, high mutation frequency (40%) in CMML | Associated with unfavorable clinical outcome in all myeloid neoplasms (MDS, MDS/MPN, MPN) |
| EZH2 | ∼5% | More often a subclonal mutation | Associated with RCMD or RAEB | Associated with unfavorable clinical outcome in all myeloid neoplasms |
| Transcription | ||||
| RUNX1 | ∼10% | Typical subclonal mutation | Associated with RCMD or RAEB | Associated with unfavorable clinical outcome |
| BCOR | <5% | Typical subclonal mutation | Associated with RCMD or RAEB | Associated with unfavorable clinical outcome |
| DNA repair control | ||||
| TP53 | ∼5% | Typical subclonal mutation | Associated with advanced disease and complex karyotype, mutated in 20% of patients with MDS with del(5q) | Associated with poor overall survival and high risk of leukemic evolution, predicts poor response to lenalidomide in MDS with del(5q) |
| Cohesin | ||||
| STAG2 | <10% | More often a subclonal mutation | Associated with RCMD or RAEB. Mutated in about 10% of patients with AML | Associated with unfavorable clinical outcome |
| RAS pathway | ||||
| CBL | <5% | More often a subclonal mutation | Found in different MDS subtypes, associated with JMML in children | Not defined in MDS |
| NRAS/KRAS | <5% | More often a subclonal mutation | Found in different MDS subtypes, associated with JMML in children | Not defined in MDS |
| NF1 | <5% | More often a subclonal mutation | Found in different MDS subtypes, associated with JMML in children | Not defined in MDS |
| DNA replication | ||||
| SETBP1 | <5% | More often a subclonal mutation | Found in 25% of patients with aCML and in subsets of patients with advanced MDS or CMML | Associated with poor overall survival and high risk of leukemic evolution |
| Receptors | ||||
| CSF3R | <1% | Founding driver mutation in CNL | Strictly associated with CNL, found in a subset of patients with aCML | Mutation type may predict response to specific inhibitors |