What is the role of cytogenetic analysis in the diagnosis and treatment of Myelodysplastic Syndrome (MDS)?

Role of Cytogenetic Analysis in the Diagnosis and Treatment of Myelodysplastic Syndrome (MDS)

Cytogenetic analysis is essential in MDS as it provides crucial diagnostic confirmation, enables accurate classification, determines prognosis, and guides treatment decisions. 1

Diagnostic Role

Establishing Clonality

• Chromosomal abnormalities are observed in 50-60% of MDS patients, confirming the clonal nature of the disease 1
• In the remaining patients with normal karyotype, sub-microscopic alterations provide the genetic basis for disease 1
• According to WHO 2008 criteria, certain recurrent cytogenetic abnormalities are considered presumptive evidence of MDS, even with minimal morphological dysplasia 1

Standard Cytogenetic Protocol

• Bone marrow aspirate cytogenetic analysis should be performed in all suspected MDS cases 1
• Analysis of at least 20-25 metaphases is recommended 1
• At least two different cell cultures (24h and 48h) should be established 1
• Documentation should follow International System for Human Cytogenetic Nomenclature (ISCN) recommendations 1

Common Cytogenetic Abnormalities

• Most frequent single abnormalities include:
  • del(5q)
  • monosomy 7 or del(7q)
  • trisomy 8
  • del(20q) 1

Prognostic Role

Risk Stratification

• Karyotype has the highest prognostic weight of all parameters in the Revised International Prognostic Scoring System (IPSS-R) 1
• Cytogenetic findings help stratify patients into different risk categories:
  • Good prognosis: normal karyotype, loss of Y chromosome, del(11q), del(12p), del(20q) as single alterations 2
  • Poor prognosis: complex karyotype, -7/7q-, i(17q) 2
  • Intermediate prognosis: rearrangements of 3q21q26, trisomy 8, trisomy 9, translocations of 11q and del(17p) 2

MDS with del(5q)

• The only cytogenetically defined MDS subtype in WHO classification 1
• Characterized by specific clinical features and generally better prognosis 1
• Requires cytogenetic analysis for diagnosis, regardless of morphology 1

Treatment Implications

Guiding Therapy Selection

• Cytogenetic findings directly influence treatment decisions:
  • Patients with del(5q) respond particularly well to lenalidomide 1
  • Complex karyotypes may indicate need for more aggressive therapy 3
  • Certain abnormalities predict response to hypomethylating agents 3

Monitoring Disease Progression

• Serial cytogenetic analyses help monitor disease evolution and treatment response 3
• Acquisition of new cytogenetic abnormalities may indicate disease progression 3

Complementary Techniques

FISH Analysis

• Useful when standard G-banding fails (absent or poor-quality metaphases) 1
• Can detect abnormalities in up to 15% of karyotypically normal MDS patients 1
• Recommended probes include 5q31, cen7, 7q31, cen8, TP53, 20q, cenY 1
• Should be used as an adjunct to conventional cytogenetics, not as a replacement 4

Molecular Genetic Analysis

• Next-generation sequencing can identify mutations in genes commonly affected in MDS:
  • Epigenetic regulators (TET2, ASXL1, DNMT3A)
  • Splicing factors (SF3B1, SRSF2, U2AF1)
  • Transcription factors (RUNX1, TP53)
  • Signaling molecules (NRAS/KRAS) 1
• Particularly useful in cases with normal cytogenetics 5
• SF3B1 mutations are associated with ring sideroblasts and generally better prognosis 1

Practical Considerations

When Conventional Cytogenetics Fails

• FISH can provide critical information when metaphase cultures fail 4
• SNP array can detect chromosomal defects with high resolution 5
• Molecular genetic testing can demonstrate clonality in cytogenetically normal cases 5

Pitfalls and Caveats

• FISH is very sensitive but can only be applied in a targeted way 1
• A comprehensive screening for all chromosomal aberrations cannot be carried out using FISH alone 1
• Some patients with normal cytogenetics may still have poor outcomes due to gene mutations not detectable by conventional cytogenetics 3

Cytogenetic analysis remains the cornerstone of MDS diagnosis and risk stratification, with emerging molecular techniques providing complementary information that enhances diagnostic accuracy and treatment planning.