Clonal Diversity and Mutated Genes in Myelodysplastic Syndromes

Myelodysplastic syndromes (MDS) are driven by somatic genetic mutations that drive clonal explansion of neoplastic cells.  The identification of these lesions has enabled large-scale studies to assess the association of genetic lesions with clinical and biological phenotype.  Single mutations in driver genes in isolation, without concurrent mutations in additional driver genes, commonly do not cause overt disease, but rather cause an expanded population of blood cells without cytopenias, a condition that we have termed clonal hematopoiesis of indeterminate potential (CHIP).   CHIP is common in the general population and is associated with age, risk of hematologic malignancy, and overall mortality.    In contrast, patients with MDS generally have mutations in multiple genes as well as the disease-defining morphologic dysplastia and peripheral blood cytopenias.  The particular mutations that drive MDS in an individual patient are powerfully associated with clinical phenotype, including cytopenias, specific morphologic abnormalities, blast percentage, overall survival, and response to therapy.  Clonal architecture adds an additional layer of complexity as disease progression or response to therapy may be associated with shifts in the dominant genetic clone in the bone marrow.  As the availability of genetic testing for panels of genes becomes widespread as a clinical assay, current endeavors are to move validated research findings into routine clinical use and to employ deep genetic analyses to evaluate response to investigational therapies in clinical trials.