Whole-genome sequencing reveals three follicular lymphoma subtypes with distinct cell of origin and patient outcomes.

Follicular lymphoma (FL) is characterized by clinical, phenotypic, and genetic heterogeneity. Here, we conduct whole-genome sequencing on 131 Chinese FL samples and identify three clinically relevant genetic subtypes. These include C1, associated with favorable prognoses and enriched for BCL6-related translocations and mutations in the NOTCH/nuclear factor κB (NF-κB)/immune evasion pathways; C2, characterized by BCL2-IGH translocations and mutations in chromatin modifiers; and C3, associated with poorer prognosis, lacking BCL2-IGH/BCL6-related translocations but exhibiting more copy number variations. We validate these subtypes in an independent Western cohort (n = 227) using the same classification strategy. Transcriptionally, C1 and C3 tumors display signatures of activated B cell-like diffuse large B cell lymphoma (DLBCL), whereas C2 tumors resemble germinal center B cell-like DLBCL. Furthermore, C1 tumors are distinguished from C3 by exhibiting gene signatures of age-associated B cells and an inflamed tumor microenvironment. Our findings illustrate the molecular heterogeneity of FL and define subtypes with distinct cell of origin and clinical outcomes, offering opportunities for personalized therapeutic strategies.