Constitutional and somatic rearrangement of chromosome 21 in acute lymphoblastic leukaemia.

Yilong Li, Claire Schwab, Sarra Ryan, Elli Papaemmanuil, Hazel M Robinson, Patricia Jacobs, Anthony V Moorman, Sara Dyer, Julian Borrow, Mike Griffiths, Nyla A Heerema, Andrew J Carroll, Polly Talley, Nick Bown, Nick Telford, Fiona Ross, Lorraine Gaunt, Richard McNally, Bryan Young, Paul SinclairVikki Rand, Manuel Teixeira, Olivia Joseph, Ben Robinson, Mark Maddison, Nicole Dastugue, Peter Vandenberghe, Claudia Haferlach, Philip Stephens, Jiqiu Cheng, Peter Van Loo, Michael Stratton, Peter Campbell, CJ Harrison

Research output: Contribution to journalArticlepeer-review


Changes in gene dosage are a major driver of cancer, known to be caused by a finite, but increasingly well annotated, repertoire of mutational mechanisms1. This can potentially generate correlated copy-number alterations across hundreds of linked genes, as exemplified by the 2% of childhood acute lymphoblastic leukaemia (ALL) with recurrent amplification of megabase regions of chromosome 21 (iAMP21)2,3. We used genomic, cytogenetic and transcriptional analysis, coupled with novel bioinformatic approaches, to reconstruct the evolution of iAMP21 ALL. Here we show that individuals born with the rare constitutional Robertsonian translocation between chromosomes 15 and 21, rob(15;21)(q10;q10)c, have approximately 2,700-fold increased risk of developing iAMP21 ALL compared to the general population. In such cases, amplification is initiated by a chromothripsis event involving both sister chromatids of the Robertsonian chromosome, a novel mechanism for cancer predisposition. In sporadic iAMP21, breakage-fusion-bridge cycles are typically the initiating event, often followed by chromothripsis. In both sporadic and rob(15;21)c-associated iAMP21, the final stages frequently involve duplications of the entire abnormal chromosome. The end-product is a derivative of chromosome 21 or the rob(15;21)c chromosome with gene dosage optimized for leukaemic potential, showing constrained copy-number levels over multiple linked genes. Thus, dicentric chromosomes may be an important precipitant of chromothripsis, as we show rob(15;21)c to be constitutionally dicentric and breakage-fusion-bridge cycles generate dicentric chromosomes somatically. Furthermore, our data illustrate that several cancer-specific mutational processes, applied sequentially, can coordinate to fashion copy-number profiles over large genomic scales, incrementally refining the fitness benefits of aggregated gene dosage changes.
Original languageEnglish
Pages (from-to)98-102
Number of pages5
Publication statusPublished - Mar 2014


Dive into the research topics of 'Constitutional and somatic rearrangement of chromosome 21 in acute lymphoblastic leukaemia.'. Together they form a unique fingerprint.

Cite this