Epistasis Between Somatic Mutations in the Normal Blood

Cancer is a disease that is the result of malignant clonal expansions, characterized by the acquisition of driver mutations. Studying the dynamics of clonal expansions in normal tissue allows for an improved understanding of how cancer arises and can potentially be prevented. Moreover, clonal expansions in normal tissue, specifically the blood, have been associated with cardiovascular disease and all-cause mortality, among many other diseases. Two leukemia-associated somatic variants in splicing factor genes, SRSF2-P95H and SF3B1-K700E, are relatively common and somatic mutations in splicing factor genes are particularly associated with the development of acute myeloid leukemia. Interestingly, these two somatic variants are also almost exclusively observed in older individuals and confer some of the highest fitness advantages, when compared to other leukemia-associated variants. This leads to the hypothesis that these two somatic variants achieve their fitness advantages through epistasis with other somatic mutations. The project will provide further insights into the clonal dynamics of SRSF2-P95H and SF3B1-K700E somatic mutations, as well as a preliminary mathematical model for epistasis between somatic mutations in normal tissue. This will hopefully help to move towards a more nuanced understanding of how somatic mutations lead to cancer.