title: Constitutional and somatic rearrangement of chromosome 21 in acute lymphoblastic leukaemia.
abstract: 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.
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK.
authors.forename: Yilong
authors.initials: Y
authors.lastname: Li
authors.affiliation: Leukaemia Research Cytogenetics Group, Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Claire
authors.initials: C
authors.lastname: Schwab
authors.affiliation: Leukaemia Research Cytogenetics Group, Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Sarra
authors.initials: S
authors.lastname: Ryan
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK.
authors.forename: Elli
authors.initials: E
authors.lastname: Papaemmanuil
authors.affiliation: West Midlands Regional Genetics Laboratory, Birmingham Women's NHS Foundation Trust, Birmingham, UK.
authors.forename: Hazel M
authors.initials: HM
authors.lastname: Robinson
authors.affiliation: Wessex Regional Genetics Laboratory, Salisbury NHS Foundation Trust, Salisbury, UK.
authors.forename: Patricia
authors.initials: P
authors.lastname: Jacobs
authors.affiliation: Leukaemia Research Cytogenetics Group, Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Anthony V
authors.initials: AV
authors.lastname: Moorman
authors.affiliation: West Midlands Regional Genetics Laboratory, Birmingham Women's NHS Foundation Trust, Birmingham, UK.|School of Cancer Sciences, University of Birmingham, Birmingham, UK.
authors.forename: Sara
authors.initials: S
authors.lastname: Dyer
authors.affiliation: West Midlands Regional Genetics Laboratory, Birmingham Women's NHS Foundation Trust, Birmingham, UK.|School of Cancer Sciences, University of Birmingham, Birmingham, UK.
authors.forename: Julian
authors.initials: J
authors.lastname: Borrow
authors.affiliation: West Midlands Regional Genetics Laboratory, Birmingham Women's NHS Foundation Trust, Birmingham, UK.|School of Cancer Sciences, University of Birmingham, Birmingham, UK.
authors.forename: Mike
authors.initials: M
authors.lastname: Griffiths
authors.affiliation: Department of Pathology, The Ohio State University, Columbus, OH.
authors.forename: Nyla A
authors.initials: NA
authors.lastname: Heerema
authors.affiliation: Department of Genetics, University of Alabama at Birmingham, Birmingham, AL.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Carroll
authors.affiliation: Sheffield Diagnostic Genetics Service, Sheffield Children's NHS Foundation Trust, Sheffield, UK.
authors.forename: Polly
authors.initials: P
authors.lastname: Talley
authors.affiliation: Cytogenetics Laboratory, Northern Genetics Service, Newcastle upon Tyne, UK.
authors.forename: Nick
authors.initials: N
authors.lastname: Bown
authors.affiliation: Oncology Cytogenetics, The Christie NHS Foundation Trust, Manchester, UK.
authors.forename: Nick
authors.initials: N
authors.lastname: Telford
authors.affiliation: Wessex Regional Genetics Laboratory, Salisbury NHS Foundation Trust, Salisbury, UK.
authors.forename: Fiona M
authors.initials: FM
authors.lastname: Ross
authors.affiliation: Regional Cytogenetics Unit, Genetic Medicine, Central Manchester University Hospitals NHS Foundation Trust, Saint Mary's Hospital, Manchester, UK.
authors.forename: Lorraine
authors.initials: L
authors.lastname: Gaunt
authors.affiliation: Institute of Health and Society, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Richard J Q
authors.initials: RJQ
authors.lastname: McNally
authors.affiliation: Leukaemia Research Cytogenetics Group, Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Bryan D
authors.initials: BD
authors.lastname: Young
authors.affiliation: Leukaemia Research Cytogenetics Group, Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Sinclair
authors.affiliation: Leukaemia Research Cytogenetics Group, Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Vikki
authors.initials: V
authors.lastname: Rand
authors.affiliation: Genetics Department, Portuguese Oncology Institute, and Biomedical Sciences Institute (ICBAS), Porto University, Portugal.
authors.forename: Manuel R
authors.initials: MR
authors.lastname: Teixeira
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK.
authors.forename: Olivia
authors.initials: O
authors.lastname: Joseph
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK.
authors.forename: Ben
authors.initials: B
authors.lastname: Robinson
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK.
authors.forename: Mark
authors.initials: M
authors.lastname: Maddison
authors.affiliation: Laboratoire d'hématologie, Génétique des Hémopathies, Hôpital Purpan, Toulouse, France.
authors.forename: Nicole
authors.initials: N
authors.lastname: Dastugue
authors.affiliation: Center for Human Genetics, University Hospital Leuven and KU Leuven, Leuven, Belgium.
authors.forename: Peter
authors.initials: P
authors.lastname: Vandenberghe
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Stephens
authors.affiliation: Center for Human Genetics, University Hospital Leuven and KU Leuven, Leuven, Belgium.|Department of Electrical Engineering - ESAT, University of Leuven, Leuven, Belgium.
authors.forename: Jiqiu
authors.initials: J
authors.lastname: Cheng
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK.|Center for Human Genetics, University Hospital Leuven and KU Leuven, Leuven, Belgium.
authors.forename: Peter
authors.initials: P
authors.lastname: Van Loo
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Stratton
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK.|Department of Haematology, University of Cambridge, Cambridge, UK.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Campbell
authors.affiliation: Leukaemia Research Cytogenetics Group, Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Christine J
authors.initials: CJ
authors.lastname: Harrison
mesh_terms: D002842:Chromatids / Q000235:genetics; D002869:Chromosome Aberrations; D019457:Chromosome Breakage; D002884:Chromosomes, Human, Pair 15 / Q000235:genetics; D002891:Chromosomes, Human, Pair 21 / Q000235:genetics*; D056915:DNA Copy Number Variations / Q000235:genetics; D006801:Humans; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*; D011995:Recombination, Genetic / Q000235:genetics; D014178:Translocation, Genetic / Q000235:genetics