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The genetic basis of transformation and progression in follicular lymphoma Kridel, Robert


The clonal evolution theory of cancer has been recognized for decades and follows principles of Darwinian selection, in which there is selection of the fittest clones in an ecosystem that is fundamentally heterogeneous and undergoes selective pressure. Follicular lymphoma (FL) emerges as a prototypical disease in which to study clonal evolution. It is the most common indolent lymphoma and, although the median overall survival largely surpasses 10 years, patients almost invariably experience progressive disease. Furthermore, a subset of FL patients is at risk of early lymphoma-related death due to rapid progression or transformation to aggressive lymphoma. Yet, the clonal dynamics and the landscape of genomic alterations underlying progression and transformation remain to be uncovered. Herein, we applied whole genome sequencing to a discovery set of transformed, progressed and non-progressed FL cases, re-constructed clonal phylogenies, and interrogated a larger set of transformed FLs and clinical extremes by capture-based targeted sequencing. Moreover, we applied the Lymph2Cx cell-of-origin assay to determine whether molecular subtypes can be defined in transformed follicular lymphoma (TFL) by gene-expression profiling. We discovered that transformation is typically the result of drastic clonal shifts during which TFL-specific clones rapidly outcompete indolent clones. In a subset of cases, these aggressive clones can be found at low levels (< 1% of tumour cells) at diagnosis. In contrast, primary progression generally results from the outgrowth of subclones that are readily detectable at diagnosis, suggesting that the genomic features conferring treatment resistance can be detected prior to initial treatment using low-pass sequencing technology. In addition, we identified discrete gene mutations that are associated with early progression and transformation, and uncovered that a subset of TFLs (16%) have an activated B-cell phenotype and are enriched for mutations in CD79B and BCL10. In summary, we found striking contrast in clonal trajectories between distinct clinical scenarios and described novel associations of gene mutations with transformation and progression. Our findings have translational relevance as they suggest that early progression, and to a lesser extent transformation, can potentially be predicted at diagnosis and thus provide a rationale for novel therapeutic approaches in TFL.

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