Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues

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Myelodysplastic Syndromes (MDS) [D46.9]

OMIM numbers: 153550, 612839 (TET2), 151385 (RUNX1), 612990 (ASXL1), 164790 (NRAS), 191170 (TP53), 600618 (ETV6), 601573 (EZH2)

Dipl.-Ing. (FH) Tanja Hinrichsen

Scientific Background

MDS represent a heterogeneous group of myeloid neoplasms which are characterized by an abnormal differentiation and maturation of myeloid cells, disorders in the bone marrow and genetic instability with increased risk for a transformation into acute myeloid leukemia (AML). They may occur de novo or after treatment (secondary). MDS are predominantly found in the elderly (incidence 20-50:100,000 in patients of the age of > 70). To establish a diagnosis, a marked and constant cytopenia (> 6 months) in at least one of the following hematopoietic cell lineages has to be present: erythroid cells (< 11 g/dL), neutrophil granulocytes (< 1,500/μL), platelets (< 100,000/μL). Furthermore, at least one of the following criteria must be fulfilled:

  • morphologic dysplasia in at least 10% of all cells in one or several cell lineages (erythroid cells, neutrophils and their precursors, megakaryocytes),
  • typical cytogenetic abnormality,
  • constant blast cell count of approx. 5-19%

Cytogenetic analysis of the bone marrow is a major component of MDS diagnostics, since cytogenetic abnormalities can provide important clues regarding classification, prognosis and treatment. Chromosomal abnormalities can be detected in 40-70% of all patients with MDS and the majority of all patients with secondary MDS. The most frequently occurring abnormalities in patients with MDS include interstitial deletions in the long arm of chromosome 5 (5q-) (30%), trisomy 8 (19%) and 7q- or monosomy 7 (15%). Additional abnormalities such as loss of the Y chromosome, 17p- and isochromosome 17 as well as interstitial deletions of chromosome 3, 11, 12, 13, and 20 occur more frequently in later stages of the disease. 10-20% of all patients with MDS exhibit what is called a complex karyotype. A normal karyotype as well as -Y, del(5q) or del(20q) have been associated with a favorable course of the disease if occurring as the only abnormality, while three or more abnormalities (complex) as well as abnormalities of chromosome 7 have been associated with an unfavorable course. Using FISH, the major abnormalities (such as deletion 5q or trisomy 8) can be detected not only on chromosomes but also on interphase nuclei and therefore also on clonal tumor cell lines.

The molecular genetic background of MDS has not been sufficiently understood yet. However, recent studies show that approximately 20% of all MDS patients have mutations in the TET2 gene. These mutations seem to be associated with a favorable prognosis, independently from the International Prognostic Scoring System (IPSS). Additionally, a decrease in the rate of AML transformation was detected. The detection of a TET2 mutation is considered to be an independent prognostic factor in MDS. In 15-20% of all MDS patients, an acquired point mutation in the RUNX1 gene is found. They exhibit a higher incidence in high-risk MDS compared to low-risk MDS and have an unfavorable prognosis; so do mutations in the ASXL1 gene (10-15%), in the NARS or KRAS gene (10-15%), the TP53 gene (5-10%), EZH2 gene (6%) and in the ETV6 gene (3%). These genes can be analyzed by next generation sequencing (NGS) in a parallel approach.

Basic Diagnostics MDS

  • Differential blood count from peripheral blood