Acquisition of genome-wide copy number alterations in monozygotic twins with acute lymphoblastic leukemia

Chimaeric fusion genes are highly prevalent in childhood acute lymphoblastic leukaemia (ALL) and are mostly pre-natal, early genetic events in the evolutionary trajectory of this cancer. ETV6-RUNX1-positive ALL also has multiple (~six per case) copy number alterations (CNA) as revealed by genome-wide SNP arrays. Recurrent CNA are probably 'driver' events contributing critically to clonal diversification and selection but, at diagnosis, their developmental timing is 'buried' in the leukaemia's covert natural history. This conundrum can be resolved with twin pairs. We identified and compared CNA in five pairs of monozygotic twins with concordant ETV6-RUNX1-positive ALL and one pair discordant for ETV6-RUNX1 positive ALL. We compared, within each pair, CNA classified as potential 'driver' or 'passenger' mutations based upon recurrency and, where known, gene function. An average of 5.1 (range 3-11) CNAs (excluding immunoglobulin/T-cell receptor alterations) were identified per case. All 'driver' CNA (total 32) were distinct within each of the five twin pairs with concordant ALL. 'Driver' CNA in another twin with ALL were all absent in the shared ETV6-RUNX1-positive pre-leukaemic clone of her healthy co-twin. These data place all 'driver' CNA secondary to the pre-natal gene fusion event and most probably post-natal in the sequential, molecular pathogenesis of ALL