Hierarchy in somatic mutations arising during genomic evolution and progression of follicular lymphoma
Menée sur des échantillons tumoraux prélevés, lors du diagnostic et à l'observation d'une récidive, sur des patients atteints d'un lymphome folliculaire, cette étude identifie des anomalies génomiques apparues de façon précoce et tardive au cours du processus de lymphomagenèse
Follicular lymphoma (FL) is currently incurable using conventional chemotherapy or immunotherapy regimes, compelling new strategies. Advances in high-throughput sequencing technologies that can reveal oncogenic pathways have stimulated interest in tailoring therapies towards actionable somatic mutations. However, for mutation-directed therapies to be most effective, the mutations must be uniformly present in evolved tumor cells as well as in the self-renewing tumor cell precursors. Here, we show striking intratumoral clonal diversity within FL tumors in the representation of mutations in the majority of genes as revealed by whole exome sequencing of subpopulations. This diversity captures a clonal hierarchy, resolved by using immunoglobulin somatic mutations and BCL2 translocations as a frame of reference and by comparing diagnosis and relapse tumor pairs, allowing us to distinguish early versus late genetic events during lymphomagenesis. We provide evidence that BCL2 translocations and CREBBP mutations are early events, while MLL2 and TNFRSF14 mutations likely represent late events during disease evolution. These observations provide insight into which of the genetic lesions represent suitable candidates for targeted therapies.