Molecular Analysis

Genetic analyses have identified mutations in genes central to the pathogenesis of myelodysplastic syndromes (MDS) and may provide diagnostic utility in MDS.1

About 90% of MDS cases have genetic mutations.1

  • Next-generation sequencing (NGS) is used to detect germline and somatic mutations in MDS2
  • Some of these mutated genes have been shown to be correlated with worse overall survival3


  • These genes can be organized into categories such as4:
  • RNA Splicing Factors Mutations within components of the spliceosome are found in up to 60% of MDS cases. The majority are in components of the 3' spliceosome, including: SF3B1, SRSF2, and U2AF1.5

    • SF3B1 mutations are the most common spliceosome alteration and are highly associated with the presence of ring sideroblasts (RS). These mutations result in altered selection of 3’ splice sites and aberrant splicing of important genes involved in iron homeostasis that mediate the RS phenotype5
    Epigenetic Regulators These include TET2, DNMT3A, IDH1, IDH2.
    Cohesin Components Encode a closed-loop multiprotein complex that normally functions to align sister chromatids during mitosis; mutations are found in 11% and 17% of low- and high-risk MDS, respectively.
    Transcription Factors Involved in hematopoietic differentiation, such as RUNX1 and GATA-2.
    DNA Damage Response Almost 40% of patients with MDS who have undergone chemotherapy have missense mutations in TP53.
    Signal Transduction Molecules These include JAK2, KRAS, NRAS, etc.
  • There are additional mutations found in patients with MDS, such as SETBP1.3 Although these mutations are rare, they are associated with poor outcomes3

Next-generation sequencing (NGS)

NGS identifies genetic variants that have been found to make a person susceptible to disease. It has been useful in sequencing a large number of novel abnormalities in cancer genomes. NGS has discovered major driver mutations in both solid and hematopoietic malignancies.6

  • With increased speed and decreased costs, NGS has the potential to improve medical care by making possible widespread evaluation of patients’ genomes in clinical settings7
  • For some patients with malignant neoplasms, NGS can improve tumor classification, diagnosis, and management. Many challenges remain, however, such as7:
    • The storage and interpretation of vast amounts of sequence data
    • Training physicians and other healthcare professionals whose knowledge of genetics may be insufficient
    • Effective genetic counseling and communication of results to patients
    • Establishing standards for the appropriate use of the technology

References: 1. Kennedy JA, Ebert BL. Clinical implications of genetic mutations in myelodysplastic syndrome. J Clin Oncol. 2017;35(9):968-974. 2. Papaemmanuil E. Somatic mutations in myelodysplastic syndrome. Blood. 2014;124:SC1-22. 3. Braggio E, Egan JB, Fonseca R, Stewart AK. Lessons from next-generation sequencing analysis in hematological malignancies. Blood Cancer J. 2013;3:e127. 4. Visconte V, Tiu RV, Rogers HJ. Pathogenesis of myelodysplastic syndromes: an overview of molecular and non-molecular aspects of the disease. Blood Res. 2014;49(4):216-227. 5. Sperling AS, Gibson CJ, Ebert BL. The genetics of myelodysplastic syndrome: from clonal hematopoiesis to secondary leukemia. Nat Rev Cancer. 2017;17(1):5-19. 6. Xuan J, Yu Y, Qing T, et al. Next-generation sequencing in the clinic: promises and challenges. Cancer Lett. 2013;340(2):284-295. 7. Johansen Taber KA, Dickinson BD, Wilson M. The promise and challenges of next-generation genome sequencing for clinical care. JAMA Intern Med. 2014;174(2):275-280.