Mutations in cell free DNA (cfDNA) or cells in the peripheral blood along with anemia or thrombocytopenia are the whole mark of myelodysplastic syndrome (MDS).
The incidence of MDS is 3-4 per 100,000 per year but increases significantly above the age of 50 and it is at 30 per 100,000 per year in patients above the age of 70. The diagnosis of MDS is confirmed when mutations in hematopoietic cells are detected at relatively high levels (>40% of cells). However, mutations at low levels in few cells can be detected in normal individuals. In general, random somatic mutations occur in normal cells, but rarely these cells evolve into viable clone, but with aging, the possibility of a clone to accumulate increases.
Clonal hematopoiesis of indeterminate potential (CHIP) is defined by the presence of low-level mutations in the peripheral blood in clinically normal individuals. CHIP is detected in 3-5% of normal individuals above the age of 50 and in approximately 10% of people aged 70 to 80. The most common mutation is on the DNMT3A gene, followed by TET2 and ASXL1. The rate of transformation to a hematological neoplasia is 0.5–1% per year. Clonal cytopenias of undetermined significance (CCUS) is defined by the presence of cytopenia (anemia, low platelets or white cells) along with low level mutations but does not meet World Health Organization (WHO)-defined criteria for MDS and the mutations are detected in <40% of cells.
Approximately 25% to 65% of patients with cytopenia will have mutation in one or more genes. These patients with mutations have significantly higher probability of developing MDS or other hematopoietic neoplasms (AML, MPN, lymphoma,…) within 5 years.
In addition, recent studies linked mutations in peripheral blood to cardiovascular disease (CVD). Recent data show that patients with CHIP have 4.0-times greater risk of myocardial infarction as compared to individuals without such clone. The prevalence of CHIP in patients with coronary artery disease is reported to be at 18.2%. In contrast, the prevalence of CHIP in centenarians is only at 2.5%. It has been shown that mutations in TET2 gene, which is one of the commonly mutated genes in CHIP, are pro-inflammatory and lead to the development of atherosclerotic plaques. Based on that it has been suggested that anti-inflammatory agents might slow the progression of cardiovascular disease in patients with low level mutations in peripheral blood.
Therefore, testing the peripheral blood for the presence of mutations provides information for:
- Diagnosis of myelodysplastic syndrome (MDS).
- Detecting the presence of mutations in the presence of cytopenia and confirming the diagnosis of clonal cytopenias of undetermined (CCUS)
- Detecting the presence of CHIP to monitor the development of hematologic neoplasms, especially MDS
- Detecting CHIP and predicting increased risk of cardiovascular disease (CVD)
Additional studies are needed to determine the clinical relevance of anti-inflammatory agents in reducing CVD or to determine the relationship between duration of the presence of CHIP or level of the mutated clone with progression of CVD or hematologic neoplasms.
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