TY - JOUR
T1 - Constitutional and somatic rearrangement of chromosome 21 in acute lymphoblastic leukaemia
AU - Li, Yilong
AU - Schwab, Claire
AU - Ryan, Sarra L.
AU - Papaemmanuil, Elli
AU - Robinson, Hazel M.
AU - Jacobs, Patricia
AU - Moorman, Anthony V.
AU - Dyer, Sara
AU - Borrow, Julian
AU - Griffiths, Mike
AU - Heerema, Nyla A.
AU - Carroll, Andrew J.
AU - Talley, Polly
AU - Bown, Nick
AU - Telford, Nick
AU - Ross, Fiona M.
AU - Gaunt, Lorraine
AU - McNally, Richard J.Q.
AU - Young, Bryan D.
AU - Sinclair, Paul
AU - Rand, Vikki
AU - Teixeira, Manuel R.
AU - Joseph, Olivia
AU - Robinson, Ben
AU - Maddison, Mark
AU - Dastugue, Nicole
AU - Vandenberghe, Peter
AU - Haferlach, Claudia
AU - Stephens, Philip J.
AU - Cheng, Jiqiu
AU - Van Loo, Peter
AU - Stratton, Michael R.
AU - Campbell, Peter J.
AU - Harrison, Christine J.
N1 - Funding Information:
Acknowledgements We thank member laboratories of the United Kingdom Cancer Cytogenetic Group (UKCCG) for providing cytogenetic data and material. Primary childhood leukaemia samples used in this study were provided by the Leukaemia and Lymphoma Research Childhood Leukaemia Cell Bank working with the laboratory teams in the Bristol Genetics Laboratory, Southmead Hospital, Bristol, UK; Molecular Biology Laboratory, Royal Hospital for Sick Children, Glasgow, UK; Molecular Haematology Laboratory, Royal London Hospital, London, UK; Molecular Genetics Service and Sheffield Children’s Hospital, Sheffield, UK. We also thank all the members of the NCRI Childhood Cancer and Leukaemia Group (CCLG) Leukaemia Subgroup for access to material and data on clinical trial patients. This work was supported by the Wellcome Trust (077012/Z/05/Z); Leukaemia and Lymphoma Research Specialist Programme and European Research Council (249891). P.J.C. has a Wellcome Trust Senior Clinical Research Fellowship (WT088340MA). P.V.L. is supported by a postdoctoral research fellowship and P.V. is a Senior Clinical Investigator funded by the Research Foundation – Flanders (F.W.O.). P.S. is funded by the European Research Council (grant 249891).
PY - 2014
Y1 - 2014
N2 - Changes in gene dosage are a major driver of cancer, known to be caused by a finite, but increasingly well annotated, repertoire of mutational mechanisms. 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). 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.
AB - Changes in gene dosage are a major driver of cancer, known to be caused by a finite, but increasingly well annotated, repertoire of mutational mechanisms. 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). 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.
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U2 - 10.1038/nature13115
DO - 10.1038/nature13115
M3 - Article
C2 - 24670643
AN - SCOPUS:84897528140
SN - 0028-0836
VL - 508
SP - 98
EP - 102
JO - Nature
JF - Nature
IS - 1
ER -