What are the causes of Myelodysplastic Syndromes (MDS)?

Causes of Myelodysplastic Syndromes (MDS)

The etiology of MDS is known in only about 15% of cases, with most cases being idiopathic, while known causes include genetic predisposition, exposure to chemotherapy agents (especially alkylating agents and purine analogues), radiation, environmental toxins like benzene, and lifestyle factors such as tobacco smoking. 1

Primary Causes of MDS

Genetic/Inherited Factors

• Inherited predisposition:
  • Seen in one-third of pediatric MDS cases 1
  • Less frequent in adults but should be assessed in:
    • Young adults with MDS
    • Families with multiple cases of MDS, AML, or aplastic anemia 1
  • Associated genetic conditions:
    • Down syndrome
    • Fanconi anemia
    • Neurofibromatosis 1
  • Specific gene mutations identified in familial cases:
    • DDX41, GATA2, RUNX1
    • ANKRD26, ETV6
    • Telomerase complex genes (TERC, TERT) 1

Environmental and Occupational Exposures

• Previous medical treatments:
  • Chemotherapy agents (therapy-related MDS)
    • Alkylating agents
    • Purine analogues 1
  • Radiotherapy or ionizing radiation 1
• Occupational exposures:
  • Benzene and its derivatives 1
  • Higher incidence reported in agricultural and industrial workers 1
• Lifestyle factors:
  • Tobacco smoking 1

Secondary MDS Characteristics

Secondary MDS (particularly therapy-related MDS) typically presents with:

• Poor prognostic factors
• Complex cytogenetic abnormalities, often involving:
  • Chromosome 5
  • Chromosome 7
  • Chromosome 17p (17p deletion) 1
• These constitute the "alkylator type" therapy-associated hematological malignancies 1

Pathophysiology of MDS Development

MDS develops through a multistep process involving:

1. Cytogenetic changes and/or gene mutations 1
2. Abnormalities of the bone marrow microenvironment 1
3. Widespread gene hypermethylation at advanced stages 1

Demographic Patterns

• Age: Predominantly affects the elderly (median age ~70 years) 1
• Incidence: Approximately 4 cases/100,000 inhabitants/year
  • Increases to 40-50/100,000 in patients aged ≥70 years 1
• Gender: More common in men than women (5.4 vs 2.9 per 100,000 yearly) 2
• Ethnic variations:
  • No known differences in overall incidence
  • In Asian populations, MDS tends to:
    • Occur at earlier ages
    • Present with hypocellular marrow more frequently
    • Have lower incidence of 5q deletion syndrome
    • Higher frequency of trisomy 8 1

Clinical Implications and Pitfalls

• Always consider MDS in elderly patients with unexplained cytopenias
• Therapy-related MDS has worse outcomes than de novo MDS, with approximately 50% classified as high/very high risk 3
• Thorough occupational and exposure history is essential in all patients with suspected MDS
• Consider genetic testing in young patients with MDS and those with family history of hematologic disorders
• Secondary MDS typically carries worse prognosis and may be more resistant to standard therapies 3

Understanding the causes of MDS is crucial for risk assessment, prognostication, and potentially for developing preventive strategies in high-risk individuals.