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Together with the studies carried out on AML, these observations raised the question of whether the presence of large DNA-damaging variants may be a reliable biomarker of aging and a marker for the emergence of cancer. These kinds of variants are common in various tissues of healthy individuals, suggesting that genetic instability may be an inherent feature of aging individuals but may also be a cause of aging and age-associated diseases in cancer cells [180] and can contribute to the development and progression of cancer. [181] AML is characterized by an increase in the number of copies of DNA acquired in the form of common mutations and of younger subclones, distal to (or derived from) driver K-RAS and N-RAS mutations, that had not been previously detected in MDS patient-derived cells [182]. One of the most well-characterized mutations is an in intron 2 G>T transition at position +1 of NRAS producing an alternative RAS splice site 299 (K299N). NRAS K299N is present in up to 20% of MDS and AML patients and enhances the transforming potential of RAS proteins. The subclonal nature of NRAS K299N in aggressive forms of AML was determined by exome sequencing [53].
Microsatellites have a great propensity to change in length. Mono-, di- and trinucleotide repeats with alleles of length longer than 20, 8 and 5 respectively, have been used as markers of clonal mutations that have a tendency to accumulate in MDS patients. Moreover, an increased number of mutations is observed in patients with higher leukocyte counts and chromosomal abnormalities. The frequency of mutations increases from a few percent of the alleles in early-stage MDS to a maximum of 20% in extensive myeloblastic leukemia with dysplasia. The relationship between disease stage, number of chromosomal abnormalities and the overall frequency of mutation was investigated in GATA2-mutated MDS patients using a PCR-based fluorescent capillary electrophoresis technique. The results showed that disease severity and the number of clones increased together with the proportion of mutated alleles [82]. d2c66b5586