Mutation, drift and selection in single-driver hematologic malignancy: Example of secondary myelodysplastic syndrome following treatment of inherited neutropenia

by Tomasz Wojdyla, Hrishikesh Mehta, Taly Glaubach, Roberto Bertolusso, Marta Iwanaszko, Rosemary Braun, Seth J. Corey, Marek Kimmel Cancer development is driven by series of events involving mutations, which may become fixed in a tumor via genetic drift and selection. This process usually includes a limited number of driver (advantageous) mutations and a greater number of passenger (neutral or mildly deleterious) mutations. We focus on a real-world leukemia model evolving on the background of a germline mutation. Severe congenital neutropenia (SCN) evolves to secondary myelodysplastic syndrome (sMDS) and/or secondary acute myeloid leukemia (sAML) in 30–40%. The majority of SCN cases are due to a germlineELANE mutation. Acquired mutations inCSF3R occur in>70% sMDS/sAML associated with SCN. Hypotheses underlying our model are: anELANE mutation causes SCN;CSF3R mutations occur spontaneously at a low rate; in fetal life, hematopoietic stem and progenitor cells expands quickly, resulting in a high probability of several tens to several hundreds of cells withCSF3R truncation mutations; therapeutic granulocyte colony-stimulating factor (G-CSF) administration early in life exerts a strong selective pressure, providing mutants with a growth advantage. Applying population genetics theory, we propose a novel two-phase model of disease development from SCN to sMDS. In Phase 1, hematopoietic tissues expand and produce tens to hundreds of stem cells with theCSF3R truncation mutation. P...
Source: PLoS Computational Biology - Category: Biology Authors: Source Type: research