What are the risk factors for Myelodysplastic Syndromes (MDS)?

Risk Factors for Myelodysplastic Syndromes (MDS)

The etiology of MDS is known in only about 15% of cases, with most cases being idiopathic, while established risk factors include age, prior chemotherapy exposure, radiation, environmental toxins like benzene, and genetic predisposition. 1

Age and Demographic Factors

• Age: MDS predominantly affects the elderly, with a median age at diagnosis of approximately 70 years 2
• Gender: Higher incidence in males compared to females (yearly incidence rates of approximately 5.4 vs 2.9 per 100,000) 3
• Incidence: Approximately 4 cases/100,000 inhabitants/year, increasing to 40-50/100,000 in patients aged ≥70 years 2
• Ethnic variations: In Asian populations, MDS tends to occur at earlier ages, presents more often with hypocellular marrow, and has a lower incidence of 5q deletion syndrome but higher frequency of trisomy 8 2

Genetic Predisposition

Inherited Syndromes

• Inherited predisposition is seen in one-third of pediatric MDS cases 1
• Less frequent in adults but should be assessed in young adults with MDS and families with multiple cases of MDS, AML, or aplastic anemia 1
• Associated genetic conditions include:
  • Down syndrome
  • Fanconi anemia
  • Neurofibromatosis 2, 1

Specific Gene Mutations

• Germline mutations identified in familial cases include:
  • DDX41
  • GATA2
  • RUNX1
  • ANKRD26
  • ETV6
  • Telomerase complex genes (TERC, TERT) 2, 1

Environmental and Occupational Exposures

Chemical Exposures

• Benzene and its derivatives: Significantly increases risk of developing MDS (OR = 1.48,95% CI: 1.00-2.19) 1, 4
• Agricultural and industrial work: Higher incidence reported in these occupations 2, 1

Lifestyle Factors

• Tobacco smoking: Former smoking status associated with increased risk of de novo MDS (OR = 1.45,95% CI: 1.10-1.93) 1, 4

Medical Treatment-Related Factors

Previous Therapies

• Chemotherapy agents:
  • Alkylating agents
  • Purine analogues 2, 1
• Radiotherapy or ionizing radiation 2, 1

Secondary MDS Characteristics

• Cases occurring after chemotherapy (therapy-related MDS) generally have poor prognostic factors
• Often present with complex cytogenetic abnormalities involving chromosomes 5,7, and/or 17p 2, 1

Medical Conditions

• Autoimmune diseases: Personal history associated with increased risk (OR = 1.34,95% CI: 0.99-1.82) 4
• Previous malignancies:
  • De novo MDS cases more commonly have history of solid tumors
  • Therapy-related MDS cases more commonly have history of hematologic malignancies 4

Pathophysiological Mechanisms

MDS develops through a multi-step process involving:

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

Clinical Implications

Understanding risk factors is crucial for:

• Early identification of high-risk individuals
• Appropriate monitoring of patients with predisposing conditions
• Potential prevention strategies in occupational settings
• Genetic counseling for families with inherited predisposition

When evaluating patients with cytopenias, a thorough assessment of these risk factors can help guide diagnostic workup and determine the likelihood of MDS versus other causes of bone marrow failure.