Of the types of genetic abnormalities found in MDS, acquired mutations in individual genes are the most recently recognized (Table 1); they are also the most frequent, currently estimated to be present in at least 80% of MDS patients. Most mutations are acquired randomly, either spontaneously (e.g., deamination of methylated cytosine to thymine), during DNA replication prior to cell division, or during DNA repair; mutations accumulate with age.
Table1. Genes Somatically Mutated in MDS
One of the central challenges of understanding the genetics of MDS has been determining which mutations contribute to the pathogenesis of the disease and which do not. While HSCs accumulate many mutations over their lifetimes, the majority are of no pathogenic consequence and are thus termed “passenger” mutations. Meanwhile, HSCs acquire nonsynonymous exonic mutations with translational consequences (“coding” mutations) at a rate of about one mutation per decade, though most of these will not affect clonal dynamics or cellular function. Since the incidence of MDS increases with age, HSCs from an average MDS patient might typically contain between 5 and 10 coding mutations, though the actual number varies widely between patients, against a background of hundreds of non coding or synonymous single nucleotide variations (SNVs). Only a minority of coding mutations, the “drivers,” actually contribute to the development of the MDS.
Although the recurrently mutated genes in MDS can be characterized in several ways, one of the simplest strategies categorizes them based on their typical position in MDS ontogeny. In this model, mutations that occur early in MDS pathogenesis, such as those in splicing factors, methylation enzymes, and certain epigenetic modifiers, are capable of driving clonal expansion, but their other phenotypic consequences are variable. Mutations that occur later in MDS development may not be capable of driving clonal expansion on their own, but their effects may complement or amplify the originating mutations, and they may be associated with clinical changes, such as worsening of cytopenias. Finally, the acquisition of activating mutations, especially within the RAS pathway, drives transformation to AML. This section is a brief summary of our current understanding of some of the most important genes and pathways that are recurrently deranged in MDS.
