Article 2014-03-23 Nature Changes in gene dosage are a major driver of cancer, engineered from 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 leukemia (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. We find that individuals born with the rare constitutional Robertsonian translocation between chromosomes 15 and 21, rob(15;21)(q10;q10)c, have ~2700-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 optimised for leukemic 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 co-ordinate to fashion copy number profiles over large genomic scales, incrementally refining the fitness benefits of aggregated gene dosage changes. 210568 oai:europepmc.org:3153735 10.1038/nature13115 24670643 210568 PMC3976272 oai:europepmc.org:3153735 true false 0.9 dedup-similarity-result wt__________::cdb54a3a00bf24cce3dc7d53722a4ce6 077012 wt__________::WT::UNKNOWN wt__________::WT::Molecules, Genes and Cells wt__________::c5c49de54218242c1abdaa7e2afe890b 088340 wt__________::WT::Molecules, Genes and Cells corda_______::f4cca6d55dd5c6dc316c6ac52501a64f 249891 ONCOGENOMICS ec__________::EC::FP7 ec__________::EC::FP7::SP2 ec__________::EC::FP7::SP2::ERC od_______908::7a7e07e14b4bdef3c9abc3e6b6a5c7ef 0.8009093 STANDARD 2013-10-29 od_______908::7a7e07e14b4bdef3c9abc3e6b6a5c7ef 0.8009093 STANDARD 2013-10-29 erc_________::5e8b9acbcb609a6bb7e1537a97a3568c 23 OliviaJoseph erc_________::eb4f41b6b769933942908e15a3080b4d 27 PeterVandenberghe erc_________::69cf9b1266dadfbcb99b6322217d127e 4 ElliPapaemmanuil erc_________::a3e526cf842ce6b18aae6ea0033e585d 3 SarraL.Ryan erc_________::7f22ed42caa8da8b7b448930873b5f79 16 FionaM.Ross erc_________::66d45e410cbd1e0c8aa384c1e0e27bea 2 ClaireSchwab erc_________::d3252f299807d524c5babdbddfd51377 9 JulianBorrow erc_________::af977d7d7b41a52177a720a26d3073e8 15 NickTelford erc_________::5dca4ebcf5226c1604603dd8f6805e3b 1 YilongLi erc_________::8db46ad4a193f4e0873120dfad2163f4 14 NickBown erc_________::8ce659ba51a8882d7689c1ae48e6bcb0 26 NicoleDastugue erc_________::f8e6e9a463c18780899e4463e6061521 22 ManuelR.Teixeira erc_________::ef8cf90ebd7b17d5f23a8520beb287e6 32 MichaelR.Stratton erc_________::d46272cccdba3f63f76b430754b89b22 30 JiqiuCheng erc_________::fdf1c6af78dcebc41ce69a0abda044da 7 AnthonyV.Moorman erc_________::f1b6ee2a07fcba85e3b685646c148ea6 11 NylaA.Heerema erc_________::a49d26bf862d07a048a27adccb0eeb78 24 BenRobinson erc_________::7ba24c1f91bc6ac79459e30545541656 33 PeterJ.Campbell erc_________::7352db75c52ffad74e015f23e30491fd 28 ClaudiaHaferlach erc_________::c296b5acc97a6c34e249cf9fc845bdc1 18 RichardJ.Q.McNally erc_________::d42a89d69c1ebb8de9c1bf9c7bfe2729 12 AndrewJ.Carroll od_______908::48b5723469fdf9be63e8f05e1a2a9647 0.8041744 STANDARD 2006-05-15 National Academy of Sciences od_______908::48b5723469fdf9be63e8f05e1a2a9647 0.8041744 STANDARD 2006-05-15 National Academy of Sciences erc_________::45b27398b13bb301b113536b6fc69dea 19 BryanD.Young erc_________::0483ae67cca91e8557a9a20ecd0fd574 31 PeterVanLoo erc_________::20fe050fd9785a1b8593799a517239e9 17 LorraineGaunt erc_________::4694f04de96c5e08ff2f55c2bb8dfd6f 25 MarkMaddison erc_________::0c892ae0aeafbf6f9ce50a5cbd7da62b 5 HazelM.Robinson erc_________::1ceec40efc00fed5bd18683275ccbdae 13 PollyTalley erc_________::440bcbc3797d6d19b61b135ee3d3cc8e 21 VikkiRand erc_________::4ab91fe4b74e6d2e1ad8fd6e211a445e 29 PhilipJ.Stephens erc_________::0b7711c1b17b4b504f43f5d844b3f80a 20 PaulSinclair erc_________::0087433d53aff83586b2ffd6f950347b 6 PatriciaJacobs erc_________::152c4c96879ac99aec22f8b19d28abee 34 ChristineJ.Harrison erc_________::1d4a72a9524b25d1cdf3e922f104fa4d 8 SaraDyer erc_________::0cb62e0d1814b0365e74d2bc9637cbb6 10 MikeGriffiths 2014-03-23 2014-03-23 http://europepmc.org/articles/PMC3976272 Beroukhim, R. 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