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Simplifying MDS Testing with Next-Generation Sequencing (NGS)

Myelodysplastic syndromes (MDS) are a heterogenous group of myeloid clonal disorders that are characterized by a failure of blood cell maturation in the bone marrow. Ineffective hematopoiesis leads to dysplasia with variable degrees of cytopenia and clonal instability.1 

According to the Surveillance, Epidemiology and End Results (SEER) program of the National Cancer Institute, the incidence rate of MDS is ~4.0 per 100,000 persons annually. A predominant risk factor for MDS is increasing age with the median age of diagnosis being between 71-76 years. The incidence rate for individuals over 75 years jumps to over 40 per 100,000 persons.2


Myelodysplastic syndromes are a form of cancer and can be more or less aggressive depending on the classification, with approximately 30% of cases progressing into acute myeloid leukemia (AML).3,4 


MDS patient risk stratification at diagnosis was previously based on blood counts, cytogenetics and morphology which were incorporated into the International Prognostic Scoring System.5 Recent guideline updates include genes mutated in MDS and outlines how this information may be used to guide risk stratification and treatment decisions.6

Molecular profiling is also becoming more important as distinguishing between cases of MDS and AML is more complex. ELN guidelines now include mutational profiles in addition to blast count in disease classification.7 Under the new guidelines, a patient can be diagnosed with AML with <20% blasts if specific genetic aberrations are present.8 

Molecular testing allows for the identification of key driver mutations in MDS, common ones include SF3B1, TET2, SRSF2, ASXL1, DNMT3A, RUNX1, U2AF1, TP53 and EZH2.9 Having a comprehensive molecular report is valuable because:

•    different genetic alterations are correlated to different clinical features, risk categories and overall survival8

•    certain mutations respond better to targeted therapies (e.g., TP53)10

•    the presence of multiple mutations with >10% variant allele frequency (VAF) is a positive predictor of neoplasia and can rule out reactive non-neoplastic etiologies11


The traditional approach to performing molecular testing involves several single-gene tests. As the number of relevant biomarkers continues to grow, this method becomes challenging and time-consuming. Advancements in next-generation sequencing (NGS) technology now allow labs to profile multiple genetic mutations at once and get results in as fast as a single day.

In a recent webinar with The Pathologist, Dr. Bevan Tandon, Chief Medical Officer at siParadigm Diagnostics, shared his experience using NGS to simplify the molecular testing of MDS samples.

To demonstrate the value of NGS, Dr. Tandon described a research case study from his lab using a sample from an 81-year-old male presenting with significant macrocytic anemia.

Initial testing with flow cytometry and chromosomal karyotyping showed no abnormalities. Morphology showed hypercellularity and iron staining indicated the presence of ring sideroblasts; however, these findings are non-specific of MDS so reactive causes could not be ruled out.

Molecular testing with NGS showed a canonical mutation in SF3B1 and two TET2 mutations with high VAF. SF3B1 mutations are very important in the characterization of MDS, especially those with ring sideroblasts.12 These mutations are known to be recurrent in 80% of MDS.

In addition, the presence of >2 pathogenic mutations with >10% VAF was highly indicative of clonal myelodysplasia. Without complete molecular profiling by NGS, these significant mutations could have been missed and resulted in misclassification of the sample as non-neoplastic. 




Watch the entire webinar from Dr. Tandon to learn how NGS can be used for the molecular profiling of AML and myeloproliferative neoplasms (MPNs), as well as myeloid measurable residual disease (MRD) detection.


Related Articles

> Genomic Profiling from Initial Assessment to Detection of Measurable Residual Disease (MRD): How NGS Can Rapidly Deliver Key Insights for Myeloid Neoplasms

> Using Next-Generation Sequencing (NGS) to Derive Key Insights in MPN Testing

> Measurable Residual Disease (MRD) in Acute Myeloid Leukemia (AML)

1. Li, H., Hu, F., Gale, R. P., Sekeres, M. A., & Liang, Y. (2022). Myelodysplastic syndromes. Nature reviews. Disease primers, 8(1), 74. https://doi.org/10.1038/s41572-022-00402-5.
2. “Myelodysplastic Syndromes (MDS) Seer.” Surveillance, Epidemiology, and End Results Program, National Cancer Institute, https://seer.cancer.gov/statistics-network/explorer/application.html?
3. Zeidan, Amer. “An Overview of Myelodysplastic Syndrome.” AJMC, AJMC, 20 May 2021, https://www.ajmc.com/view/an-overview-of-myelodysplastic-syndrome.
4. “Myelodysplastic Syndrome (MDS) Research Funded by LLS.” Myelodysplastic Syndrome (MDS) Research Funded by LLS, Leukemia and Lymphoma Society, 2018, https://www.lls.org/research/myelodysplastic-syndrome-mds-research-funded-lls.
5. Greenberg PL, Tuechler H, Schanz J, et al. Revised international prognostic scoring system for myelodysplastic syndromes. Blood2012; 120:2454–2465. DOI: 10.1182/blood-2012-03-420489.
6.    Bernard E, Tuechler H, Greenberg PL, et al. Molecular international prognostic scoring system for myelodysplastic syndromes. NEJM Evid 2022; 1 (7). DOI: https://doi.org/10.1056/EVIDoa2200008.
7.    Estey, Elihu, et al. “Distinguishing AML from MDS: A Fixed Blast Percentage May No Longer Be Optimal.” American Society of Hematology, Blood, 20 Jan. 2022, https://ashpublications.org/blood/article/139/3/323/476130/Distinguishing-AML-from-MDS-a-fixed-blast?utm_source=TrendMD&amp;utm_medium=cpc&amp;utm_campaign=Blood_TrendMD_0.
8.    Döhner, Hartmut, et al. “Diagnosis and Management of AML in Adults: 2022 Recommendations from an International Expert Panel on Behalf of the ELN.” American Society of Hematology, Blood, 22 Sept. 2022, https://ashpublications.org/blood/article/140/12/1345/485817/Diagnosis-and-management-of-AML-in-adults-2022.
9.    Dotson, J.L. “Myelodysplastic Syndrome”. NIH Natl Library of Med. https://www.ncbi.nlm.nih.gov/books/NBK534126/
10.    Swoboda, David M, and David A Sallman. “Mutation-Driven Therapy in MDS.” U.S. National Library of Medicine, Current Hematologic Malignancy Reports, 14 Dec. 2019, https://pubmed.ncbi.nlm.nih.gov/31760573/.
11.    Malcovati, Luca, et al. “Clinical Significance of Somatic Mutation in Unexplained Blood Cytopenia.” American Society of Hematology, Blood, 22 June 2017, https://ashpublications.org/blood/article/129/25/3371/107625/Clinical-significance-of-somatic-mutation-in.
12.    Malcovati, Luca, et al. “SF3B1 Mutation Identifies a Distinct Subset of Myelodysplastic Syndrome with Ring Sideroblasts.” American Society of Hematology, Blood, 9 July 2015, https://ashpublications.org/blood/article/126/2/233/34510/SF3B1-mutation-identifies-a-distinct-subset-of.


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