Genetic and molecular characterization of myelodysplastic syndromes and related myeloid neoplasms

Whole exome next generation sequencing systematically applied as a discovery tool in myelodysplastic syndromes (MDS) has led to the identification of a large number of novel mutations. Despite hundreds of patients studied, mutational saturation has not been reached and it is expected that new driver mutations will be discovered in this very heterogeneous condition. Serial samples and deep sequencing of the identified alterations has allowed for a dynamic/chronologic analysis of clonal architecture and identification of a subset of ancestral and secondary molecular lesions. Chromosomal gains and losses have been incorporated into the mutational analyses because they can either cooperate with mutations or produce a functional phenocopy. In addition to the search for somatic defects in MDS, similar discovery studies have been also performed to identify germ line mutations/alterations. Clinical analysis showed applicability of multiplexed somatic mutational panels that would complement current pathomorphologic diagnosis, allow for subclassification of nosologic entities, and enhance predictive power of current prognostic algorithms. Overall, comprehensive genomic analysis in MDS has revealed a tremendous heterogeneity of somatic lesions and their combinations further enhanced by the heterogeneity of clonal architecture and chromosomal lesions.