Molecular Profiling of Myelodysplastic Syndromes

Myelodysplastic syndromes (MDS) are a group of myeloid neoplasms originating in hematopoietic stem cells, characterized by ineffective hematopoiesis and an increased risk of progression to acute myeloid leukemia (AML). This aberrant hematopoiesis manifests clinically as cytopenias and morphologically as dysplasia. MDS is primarily a disease of the elderly, with a median age of 76 at diagnosis (Ma et al. 2007; Tefferi and Vardiman 2009). In the United States, more than 10,000 cases of MDS are diagnosed each year (Ma et al. 2007), although this incidence is likely underestimated due to the difficulty in making a definitive diagnosis of MDS. In the United States, the 3-year observed survival rate for all types of MDS is 35% (Ma et al. 2007).

There are several types of MDS, shown in Table 1, grouped according to classification system.

Table 1. Types of MDS by Classification System.
Myelodysplastic Syndromes Classification System
WHO 2008a FAB 1982b SEERc
Refractory cytopenia with unilineage dysplasia (RCUD)
Refractory anemia (RA)
Refractory neutropenia (RN)
Refractory thrombocytopenia (RT)
Refractory anemia with ring sideroblasts (RARS)
Refractory cytopenia with multilineage dysplasia (RCMD)
Refractory anemia with excess of blasts (RAEB)
RAEB-1
RAEB-2
Myelodysplastic syndrome with isolated del(5q)
Myelodysplastic syndrome (unclassifiable)
NOTE: a WHO = World Health Organization; Tefferi and Vardiman 2009. b FAB = French–American–British; Tefferi and Vardiman 2009. c SEER = Surveillance, Epidemiology, and End Results database. While SEER is not a classification system, it is included since SEER is the primary source of information available about prevalence and mortality of MDS in the United States, and their categories do not map directly to either WHO or FAB (classification is based on ICD-O-3 codes; Ma et al. 2007).

Treatment of MDS depends on subtype and prognostic category. There are several prognostic classifications in use, with IPSS-R being the most current (Greenberg et al. 2012). Lower risk asymptomatic MDS is typically treated with only supportive care, while symptomatic lower risk MDS may be treated with hematopoietic growth factors (epoetin alfa, darbepoetin alfa), DNA methyltransferase inhibitors (azacitidine or decitabine), immunosuppressive therapy (antithymocyte globulin), or lenalidomide (NCCN 2014; Schrier et al. 2014). Lenalidomide is approved for patients with 5q minus syndrome while the DNA methyltransferase inhibitors are approved for high risk MDS. For some high risk patients, combination chemotherapy, such as that used in the treatment of AML, may be considered. Allogenic hematopoietic stem cell transplant or combination chemotherapy may be used to treat high risk patients or for patients who have failed other treatments. (NCCN 2014; Schrier et al. 2014).

Several genetic surveys of MDS have revealed that genes along several cellular pathways can be involved in MDS (Haferlach et al. 2014; Walter et al. 2013). These include genes producing proteins involved in RNA splicing, DNA methylation, chromatin modification, transcription, DNA repair control, cohesin function, the RAS pathway, and DNA replication (Cazzola, Della Porta, and Malcovati 2013). There is significant overlap between the genes mutated commonly in MDS with those found in AML, although their relative frequencies are quite different, with more frequent spliceosome mutations in MDS and more mutations in FLT3 and NPM1 in AML (Walter et al. 2013).

Currently, knowledge of cytogenetic abnormalities or gene mutations can be used as an aid in diagnosis of MDS. Mutations in several genes have been shown to have prognostic significance; these include ASXL1, BCOR, ETV6, EZH2, RUNX1, TET2, and TP53 (Bejar et al. 2011; Cazzola, Della Porta, and Malcovati 2013; Damm et al. 2013; Kosminder et al. 2009; NCCN 2014; Thol et al. 2011; Thol et al. 2012; Zhang et al. 2012). Others have been associated with decreased or improved outcomes, although the associations have not been shown to be statistically significant: DNMT3A, SF3B1, SRSF2, STAG2, U2AF1, and ZRSR2 (Bejar et al. 2012; Cazolla, Della Porta, and Malcovati 2013; Damm et al. 2012; Graubert et al. 2011; Makishima et al. 2012; Malcovati et al. 2011; NCCN 2014; Thol et al. 2012; Walter et al. 2011). Mutation status is not yet used to select treatments in MDS. However, Cazzola, Della Porta, and Malcovati (2013) note several types of targeted therapies that show promise for use in MDS, including epigenetic-targeting therapies, spliceosome-targeting therapies, and Ras-targeting therapies.​

Contributors: Stephen A. Strickland, M.D., MSCI, Annette S. Kim, M.D., Ph.D.

Suggested Citation: Strickland, S., A. Kim. 2014. Molecular Profiling of Myelodysplastic Syndromes. My Cancer Genome https://www.padiracinnovation.org/content/disease/myelodysplastic-syndromes/ (Updated September 23).

Last Updated: September 23, 2014

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