Follicular lymphoma is an incurable malignancy, with transformation to an aggressive
subtype representing a critical event during disease progression. Here we performed
whole-genome or whole-exome sequencing on 10 follicular lymphoma-transformed follicular
lymphoma pairs followed by deep sequencing of 28 genes in an extension cohort, and
we report the key events and evolutionary processes governing tumor initiation and
transformation. Tumor evolution occurred through either a 'rich' or 'sparse' ancestral
common progenitor clone (CPC). We identified recurrent mutations in linker histone,
JAK-STAT signaling, NF-κB signaling and B cell developmental genes. Longitudinal analyses
identified early driver mutations in chromatin regulator genes (CREBBP, EZH2 and KMT2D
(MLL2)), whereas mutations in EBF1 and regulators of NF-κB signaling (MYD88 and TNFAIP3)
were gained at transformation. Collectively, this study provides new insights into
the genetic basis of follicular lymphoma and the clonal dynamics of transformation
and suggests that personalizing therapies to target key genetic alterations in the
CPC represents an attractive therapeutic strategy.
