ALBERT

Description: 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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3976272/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3976272/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Li, Yilong -- Schwab, Claire -- Ryan, Sarra L -- Papaemmanuil, Elli -- Robinson, Hazel M -- Jacobs, Patricia -- Moorman, Anthony V -- Dyer, Sara -- Borrow, Julian -- Griffiths, Mike -- Heerema, Nyla A -- Carroll, Andrew J -- Talley, Polly -- Bown, Nick -- Telford, Nick -- Ross, Fiona M -- Gaunt, Lorraine -- McNally, Richard J Q -- Young, Bryan D -- Sinclair, Paul -- Rand, Vikki -- Teixeira, Manuel R -- Joseph, Olivia -- Robinson, Ben -- Maddison, Mark -- Dastugue, Nicole -- Vandenberghe, Peter -- Haferlach, Claudia -- Stephens, Philip J -- Cheng, Jiqiu -- Van Loo, Peter -- Stratton, Michael R -- Campbell, Peter J -- Harrison, Christine J -- 077012/Z/05/Z/Wellcome Trust/United Kingdom -- 088340/Wellcome Trust/United Kingdom -- 093867/Wellcome Trust/United Kingdom -- U10 CA098543/CA/NCI NIH HHS/ -- U10 CA180886/CA/NCI NIH HHS/ -- WT088340MA/Wellcome Trust/United Kingdom -- England -- Nature. 2014 Apr 3;508(7494):98-102. doi: 10.1038/nature13115. Epub 2014 Mar 23.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK [2]. ; 1] Leukaemia Research Cytogenetics Group, Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne NE2 4HH, UK [2]. ; Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK. ; West Midlands Regional Genetics Laboratory, Birmingham Women's NHS Foundation Trust, Birmingham B15 2TG, UK. ; Wessex Regional Genetics Laboratory, Salisbury NHS Foundation Trust, Salisbury SP2 8BJ, UK. ; Leukaemia Research Cytogenetics Group, Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne NE2 4HH, UK. ; 1] West Midlands Regional Genetics Laboratory, Birmingham Women's NHS Foundation Trust, Birmingham B15 2TG, UK [2] School of Cancer Sciences, University of Birmingham, Birmingham B15 2TT, UK. ; Department of Pathology, The Ohio State University, Columbus, Ohio 43210, USA. ; Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama 35233, USA. ; Sheffield Diagnostic Genetics Service, Sheffield Children's NHS Foundation Trust, Sheffield S10 2TH, UK. ; Cytogenetics Laboratory, Northern Genetics Service, Newcastle upon Tyne NE7 7DN, UK. ; Oncology Cytogenetics, The Christie NHS Foundation Trust, Manchester M20 4BX, UK. ; Regional Cytogenetics Unit, Genetic Medicine, Central Manchester University Hospitals NHS Foundation Trust, Saint Mary's Hospital, Manchester M13 9WL, UK. ; Institute of Health and Society, Newcastle University, Newcastle upon Tyne NE2 4AX, UK. ; 1] Genetics Department, Portuguese Oncology Institute, Porto University, 4200-072 Porto, Portugal [2] Biomedical Sciences Institute (ICBAS), Porto University, 4200-072 Porto, Portugal. ; Laboratoire d'Hematologie, Genetique des Hemopathies, Hopital Purpan, 31059 Toulouse, France. ; 1] Center for Human Genetics, University Hospital Leuven, 3000 Leuven, Belgium [2] KU Leuven, 3000 Leuven, Belgium. ; MLL Munich Leukemia Laboratory, Munich 81377, Germany. ; 1] Center for Human Genetics, University Hospital Leuven, 3000 Leuven, Belgium [2] KU Leuven, 3000 Leuven, Belgium [3] Department of Electrical Engineering - ESAT, University of Leuven, 3000 Leuven, Belgium. ; 1] Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK [2] Center for Human Genetics, University Hospital Leuven, 3000 Leuven, Belgium [3] KU Leuven, 3000 Leuven, Belgium. ; 1] Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK [2] Department of Haematology, University of Cambridge, Cambridge CB2 2XY, UK [3].〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24670643" target="_blank"〉PubMed〈/a〉