Single-cell whole-genome sequencing reveals convergent evolution in Burkitt lymphoma
Steemers, A. S.; van Roosmalen, M. J.; Hagelaar, R.; Trabut, L.; Verheul, M.; Jongsma, S.; de Kanter, J. K.; Meyer-Wentrup, F.; van Boxtel, R.
Show abstract
Burkitt lymphoma (BL) carries multiple oncogenic drivers yet arises predominantly in children, whose normal cells harbour few age-related mutations. To investigate this paradox, we sought to define the sequence and timing of mutational drivers underlying BL development. Here, we analysed single-cell whole-genome sequencing (WGS) data of 250 paired normal and malignant B-cells from BL patients and integrated this data with 21 bulk WGS samples and an existing dataset of 157 clonally expanded B-cells from healthy individuals. Phylogenetic reconstruction revealed an accelerated accumulation of mutations following the emergence of the most recent common ancestor, leading to the early establishment of extensive genetic intra-tumoral heterogeneity. We further provide evidence that convergent evolution shapes this diversity at both the point mutation- and copy number variation-levels. This in-depth characterisation further establishes BL as a paradigmatic model of tumorigenesis with implications for therapeutic intervention.
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