Genetics of Follicular Lymphoma Transformation

• FL and tFL arise from a common mutated precursor clone by divergent evolution
• Epigenetic modifiers and antiapoptotic genes are mutated in the common precursor
• Biallelic disruption of CDKN2A/B and deregulation of MYC are specific to tFL
• tFL displays a unique genomic profile with only partial similarity to DLBCL

SummaryFollicular lymphoma (FL) is an indolent disease, but 30%–40% of cases undergo histologic transformation to an aggressive malignancy, typically represented by diffuse large B cell lymphoma (DLBCL). The pathogenesis of this process remains largely unknown. Using whole-exome sequencing and copy-number analysis, we show here that the dominant clone of FL and transformed FL (tFL) arise by divergent evolution from a common mutated precursor through the acquisition of distinct genetic events. Mutations in epigenetic modifiers and antiapoptotic genes are introduced early in the common precursor, whereas tFL is specifically associated with alterations deregulating cell-cycle progression and DNA damage responses (CDKN2A/B, MYC, and TP53) as well as aberrant somatic hypermutation. The genomic profile of tFL shares similarities with that of germinal center B cell-type de novo DLBCL but also displays unique combinations of altered genes with diagnostic and therapeutic implications.

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