Table 1.
Genetic Abnormalities in MDS
| Genetic Abnormality | Frequency (%) | Pathogenic Mechanism | Clinical Consequence |
|---|---|---|---|
| Chromosomal abnormalities | |||
| 5q- | 15 | Haploinsufficiency for RPS14, miR-145/146a, CTNNA1, EGR1, APC, NPM | Better prognosis, high rate of response to lenalidomide |
| -7/7q- | 5-10 | Unknown | Poor prognosis, more common in therapy-related MDS |
| Trisomy 8 | 5-8 | Unknown | Can help predict response to immunosuppression, some evidence as a marker of progression to AML |
| 20q- | 2-5 | Unknown | Better prognosis |
| -Y | 2-4 | Age-related phenomenon that may not be disease related | May be useful as a marker of clonal hematopoiesis |
| Complex (three or more abnormalities) | 10-15 | Various; often abnormal chromosome 17 (TP53 locus) | Poor prognosis |
| -13/13q-, 11q-, 12p-, 9q-, idic(X)(q13), i(17q), t(11;16), t(3;21), t(1;3), t(2;11), inv(3), t(6;9) | Rare | Various, mostly unknown; chromosome 3q26 lesions alter expression of EVI1 | Presumptive evidence of MDS in patients with otherwise unexplained refractory cytopenia and no morphologic evidence of dysplasia |
| Gene mutations | |||
| TET2 | Approximately 20 | Unknown | Unknown |
| RUNX1 | 15-20 | Mutations typically alter DNA-binding domain or disrupt protein-binding domain | Increased risk of progression to AML; more common in therapy-related MDS |
| TP53 | 5-10 | Loss of function of p53 tumor suppressor activity; associated with chromosomal instability | Often complex cytogenetics, relative resistance to therapy, poor prognosis |
| ASXL1 | 10-15 | Unknown; most mutations are distal heterozygous frame shifts, suggesting a dominant negative function | Unknown |
| NRAS/KRAS | Approximately 10 | Loss of GTPase activity leads to constitutive activation of serine/threonine kinase | Increased risk of progression to AML |
| EZH2 | 6 | Loss of histone 3 lysine 27 methyltransferase activity | Poor prognosis |
| CBL/CBLB | Rare | Loss of ubiquitin ligase activity; mutants can inhibit wild-type enzymatic function | Unknown; increased risk of progression to leukemia in MPN and in CMML where this mutation is more common |
| JAK2 | 5% of RA, 50% of RARS-T | Constitutive activation of tyrosine kinase | Unknown; does not appear to alter prognosis |
| MPL | 5% of RARS-T | Constitutive activation of tyrosine kinase | Unknown |
| ATRX | Rare | Loss of function leads to decreased alpha-globin expression, likely through epigenetic dysregulation | Acquired alpha-thalassemia, often with very severe anemia |
| NPM1 | Rare | Terminal frame shift disrupts nucleolar localization signal leading to cytoplasmic redistribution of protein | Unknown; this mutation is very common in AML with normal cytogenetics |
| IDH1, IDH2 | Rare | Missense mutations alter catalytic function to convert α-ketoglutarate into 2-hydroxyglutarate while consuming NADPH | Associated with more advanced disease and progression to AML |
| CEBPA | Rare | Loss of function known to impair granulopoiesis | Unknown; germline mutations associated with risk of AML, not MDS |
| WT1 | Very rare | Impairment of transcription factor activity | Unknown; mutations are more common in AML and associated with poor outcomes |
| PTPN11 | Very rare | Alters function of gene product SHP2, an adaptor protein with tyrosine phosphatase activity | More common in JMML, rare in CMML |
| FLT3, CSF1R, CKIT | Very rare | Constitutive activation of tyrosine kinase | Associated with more advanced disease and progression to AML |
NOTE. Rare mutations are present in 2% to 5% of patients; very rare refers to individual reports or < 2% of patients.
Abbreviations: MDS, myelodyplastic syndromes; CTNNA1, alpha-catenin 1; EGR1, early growth response 1; APC, adenomatous polyposis coli; NPM1, nucleophosmin 1; AML, acute myeloid leukemia; GTPase, guanosine triphosphatase; MPN, myeloproliferative neoplasms; CMML, chronic myelomonocytic leukemia; NADPH, nicotinamide adenine dinucleotide phosphate; JMML, juvenile myelomonocytic leukemia.