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Constitutional and somatic genomic rearrangements coherently restructure chromosome 21 in acute lymphoblastic leukaemia

Changes in gene dosage are a major driver of cancer1, engineered from a finite, but increasingly well annotated, repertoire of mutational mechanisms2-6. These processes operate over levels ranging from individual exons to whole chromosomes, often generating correlated copy number alterations across hundreds of linked genes. An example of the latter is the 2% of childhood acute lymphoblastic leukemia (ALL) characterized by recurrent intrachromosomal amplification of megabase regions of chromosome 21 (iAMP21)7,8 To dissect the interplay between mutational processes and selection on this scale, 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 chromothripsis involving both sister chromatids of the dicentric Robertsonian chromosome. In contrast, sporadic iAMP21 is typically initiated by breakage-fusion-bridge (BFB) events, often followed by chromothripsis or other rearrangements. In both sporadic and iAMP21 in rob(15;21)c individuals, the final stages of amplification frequently involve large-scale duplications of the abnormal chromosome. The end-product is a derivative chromosome 21 or a derivative originating from the rob(15;21)c chromosome, der(15;21), respectively, with gene dosage optimised for leukemic potential, showing constrained copy number levels over multiple linked genes. In summary, the constitutional translocation, rob(15;21)c, predisposes to leukemia through a novel mechanism, namely a propensity to undergo chromothripsis, likely related to its dicentric nature. More generally, 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.

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Studies are experimental investigations of a particular phenomenon, e.g., case-control studies on a particular trait or cancer research projects reporting matching cancer normal genomes from patients.

Study ID Study Title Study Type
EGAS00001000058 Cancer Genomics
EGAS00001000209 Cancer Genomics

This table displays only public information pertaining to the files in the dataset. If you wish to access this dataset, please submit a request. If you already have access to these data files, please consult the download documentation.

ID File Type Size Located in
EGAF00000065213 bam 11.6 GB
EGAF00000065214 bam 9.9 GB
EGAF00000065216 bam 11.5 GB
EGAF00000071423 bam 3.8 GB
EGAF00000071424 bam 3.1 GB
EGAF00000071425 bam 3.8 GB
EGAF00000071426 bam 3.5 GB
EGAF00000127383 bam 3.1 GB
EGAF00000127384 bam 6.7 GB
EGAF00000127385 bam 7.6 GB
EGAF00000127386 bam 6.5 GB
EGAF00000166868 bam 5.3 GB
EGAF00000166869 bam 10.0 GB
EGAF00000166870 bam 10.6 GB
EGAF00000166871 bam 9.3 GB
EGAF00000166872 bam 5.3 GB
EGAF00000166873 bam 10.2 GB
EGAF00000166874 bam 10.7 GB
EGAF00000166875 bam 9.4 GB
EGAF00000167838 bam 20.9 GB
EGAF00000168412 bam 18.6 GB
EGAF00000168413 bam 15.1 GB
EGAF00000168461 bam 19.0 GB
23 Files (215.6 GB)