Abstract

Significance Follicular lymphoma (FL) is a disease characterized by multiple relapses that are linked by a common progenitor bearing only a subset of the mutations found within the tumor that presents clinically. Inability to cure this disease may therefore be linked to the failure of current therapies to clear these early tumor-propagating clones. Here we further define the genetic hallmarks of this disease and model the steps in evolution through phylogenetic analysis of serial tumor biopsies. This identified CREBBP mutations as early events in genome evolution that are enriched within tumor cell progenitors and provided evidence that these mutations act by allowing immune evasion. This highlights CREBBP mutations as an attractive therapeutic target in FL and provides insight into their pathogenic mechanism.