Follicular lymphoma (FL) is incurable with conventional
therapies and has a
clinical course typified by multiple relapses after
therapy. These
tumors are genetically characterized by
B-cell leukemia/
lymphoma 2 (BCL2) translocation and mutation of genes involved in
chromatin modification. By analyzing purified
tumor cells, we identified additional novel recurrently mutated genes and confirmed mutations of one or more
chromatin modifier genes within 96% of FL
tumors and two or more in 76% of
tumors. We defined the hierarchy of somatic mutations arising during
tumor evolution by analyzing the phylogenetic relationship of somatic mutations across the coding genomes of 59 sequentially acquired biopsies from 22 patients. Among all somatically mutated genes, CREBBP mutations were most significantly enriched within the earliest inferable progenitor. These mutations were associated with a signature of decreased antigen presentation characterized by reduced transcript and
protein abundance of MHC class II on
tumor B cells, in line with the role of CREBBP in promoting
class II transactivator (CIITA)-dependent transcriptional activation of these genes. CREBBP mutant B cells stimulated less proliferation of T cells in vitro compared with wild-type B cells from the same
tumor. Transcriptional signatures of
tumor-infiltrating T cells were indicative of reduced proliferation, and this corresponded to decreased frequencies of
tumor-infiltrating CD4 helper T cells and CD8 memory cytotoxic T cells. These observations therefore implicate CREBBP mutation as an early event in FL evolution that contributes to immune evasion via decreased antigen presentation.