Myelodysplastic Syndromes (MDS)

Myelodysplastic syndromes (MDS) are a group of rare hematological cancers affecting the production of normal blood cells in the bone marrow. Damage to the DNA of hematopoietic stem cells results in the formation of immature, dysfunctional blood cells, including erythrocytes, leukocytes, and platelets.¹

Many factors increase the risk for MDS, including older age, male sex, genetic mutations, environmental exposures, and prior treatments.²

Age Risk Factors

Epidemiological studies have revealed that the risk of MDS increases sharply with age. MDS is rare in children.² Onset before the age of 50 is atypical and usually related to prior cancer treatments.³ Most cases of MDS occur after the age of 60, with the largest majority appearing in individuals ages 70 to 80.^2,3

Read more about MDS epidemiology

Sex Risk Factors 

Studies indicate that the risk for most subtypes of MDS is greater in men than in women. MDS with isolated deletion of chromosome 5q is an exception.^{2,4 (3)}

Genetic Risk Factors

Somatic genetic changes acquired over a lifetime typically increase the risk of MDS. Many mutations have been shown to increase the risk for MDS, and further links are expected to be discovered.⁵ 

Several inherited genetic variants, called germline predispositions, are also associated with an increased risk for MDS. MDS due to germline predispositions presents more commonly in younger adults or children.^2,5

Myeloid neoplasms with germline predisposition without a pre-existing platelet disorder or organ dysfunction

Myeloid neoplasms are associated with germline pathogenic or likely pathogenic variations in the following genes²:

• CEBPA, causing CEBPA-associated familial acute myeloid leukemia (AML)
• DDX41
• TP53, causing Li-Fraumeni syndrome

Myeloid neoplasms with germline predisposition and pre-existing platelet disorder

Myeloid neoplasms are associated with germline pathogenic or likely pathogenic variations in the following genes²:

• RUNX1, causing familial platelet disorder with associated myeloid malignancy
• ANKRD26, causing thrombocytopenia 2
• ETV6, causing thrombocytopenia 5

Myeloid neoplasms with germline predisposition and potential organ dysfunction

Myeloid neoplasms are associated with germline pathogenic or likely pathogenic variations in the following genes and genetic disorders²:

• Biallelic BLM variants, causing Bloom syndrome
• GATA2, causing GATA2-deficiency
• SAMD9, causing MIRAGE syndrome
• SAMD9, causing SAMDL-related ataxia pancytopenia syndrome
• Bone marrow failure syndromes, including Diamond Blackfan anemia, dyskeratosis congenita, Fanconi anemia, severe congenital neutropenia, and Shwachman-Diamond syndrome^2,3
• Down syndrome
• RASopathies, including Casitas B-lineage lymphoma (Cbl) syndrome, neurofibromatosis type 1, Noonan syndrome, or Noonan syndrome-like disorders
• Telomere disorders

Read more about MDS genetics

In 2022, the World Health Organization (WHO) published new guidelines for the classification of MDS by establishing 2 new groups: MDS with defining genetic abnormalities and MDS, morphologically defined.⁶ The former category includes 3 subtypes⁷: 

• MDS with low blasts and isolated 5q deletion
• MDS with low blasts and SF3B1 mutation
• MDS with biallelic TP53 inactivation

Read more about MDS types

Risk Factors Related to Environmental Exposures

Long-term occupational or environmental exposures to various substances may alter the genetic material of hematopoietic stem cells. These exposures may include^2,3:

• Benzene or other chemicals used in the rubber and petroleum industries; 
• Insecticides;
• Smoking, especially tobacco smoke; and
• Toxins.

Some studies indicate that survivors of the atomic bomb explosions in Nagasaki and Hiroshima in 1945 have genetic abnormalities associated with an increased risk for MDS.^8-10 Genomic analysis has revealed changes affecting chromosomes 3, 8, and 11, especially 11q, TP53, and ATM variants.⁸ 

Exposure to nuclear reactor accidents also may predispose people to MDS.⁵ This subtype of MDS is classified as secondary MDS because radiation has altered the DNA of hematopoietic stem cells.¹⁰ 

Read more about MDS prognosis

Risk Factors Related to Previous Treatments 

Approximately 20% of people in whom MDS develops report a history of chemotherapy or radiation therapy. Treatment-related MDS, another form of secondary MDS, may develop in individuals at much younger ages than other MDS subtypes.^2,3,10

Some chemotherapy agents that may lead to MDS include³:

• Doxorubicin (sold as Adriamycin^® and Rubex^®);
• Cytoxan^® (cyclophosphamide);
• Etoposide (sold as Etopophos^® and VePesid^®);
• Ifex^® (ifosfamide);
• Leukeran^® (chlorambucil);
• Matulane^® (procarbazine);
• Mustargen^® (mechlorethamine, also known as nitrogen mustard); and
• Vumon^® (teniposide).

The risk for treatment-related MDS depends on the type and dose of chemotherapy administered and whether chemotherapy was combined with radiation treatments.³

Read more about MDS treatment

References

1. Myelodysplastic syndrome. MedlinePlus. Accessed June 11, 2023.
2. Myelodysplastic syndromes – MDS: risk factors. Cancer.Net. Accessed June 11, 2023.
3. Risk factors for myelodysplastic syndromes. American Cancer Society. Accessed June 11, 2023.
4. Myelodysplastic syndrome with isolated del(5q). National Cancer Institute SEER Program. Accessed June 11, 2023.
5. Kennedy AL, Shimamura A. Genetic predisposition to MDS: clinical features and clonal evolution. Blood. 2019;133(10):1071-1085. doi:10.1182/blood-2018-10-844662
6. Khoury JD, Solary E, Abla O, et al. The 5th edition of the World Health Organization classification of haematolymphoid tumours: myeloid and histiocytic/dendritic neoplasms. Leukemia. 2022;36(7):1703-1719. doi:10.1038/s41375-022-01613-1
7. Khoury JD, Solary E, Abla O, et al. Table 3. Classification and defining features of myelodysplastic neoplasms (MDS). Leukemia. 2022;36(7):1703-1719. doi:10.1038/s41375-022-01613-1
8. Taguchi M, Mishima H, Shiozawa Y, et al. Genome analysis of myelodysplastic syndromes among atomic bomb survivors in Nagasaki. Haematologica. 2020;105(2):358-365. doi:10.3324/haematol.2019.219386
9. Hata T, Imanishi D, Miyazaki Y. Lessons from the atomic bomb about secondary MDS. Curr Hematol Malig Rep. 2014;9(4):407-411. doi:10.1007/s11899-014-0235-0
10. Iwanaga M, Hsu WL, Soda M, et al. Risk of myelodysplastic syndromes in people exposed to ionizing radiation: a retrospective cohort study of Nagasaki atomic bomb survivors. J Clin Oncol. 2011;29(4):428-434. doi:10.1200/JCO.2010.31.3080

Reviewed by Kyle Habet, MD, on 6/16/2023.

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Maria Arini Lopez, PT, DPT, CSCS, CMTPT, CIMT

Maria Arini Lopez, PT, DPT, CSCS, CMTPT, CIMT is a freelance medical writer and Doctor of Physical Therapy from Maryland. She has expertise in the therapeutic areas of orthopedics, neurology, chronic pain, gastrointestinal dysfunctions, and rare diseases especially Ehlers Danlos Syndrome.