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Nat Genet. 2014 Feb;46(2):116-25. doi: 10.1038/ng.2874. Epub 2014 Jan 12.

RAG-mediated recombination is the predominant driver of oncogenic rearrangement in ETV6-RUNX1 acute lymphoblastic leukemia.

Author information

1
Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK.
2
Hospital Universitario 12 de Octubre, Madrid, Spain.
3
Institute for Cancer Research, Sutton, London, UK.
4
1] Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK. [2] Department of Human Genetics, VIB and University of Leuven, Leuven, Belgium.
5
1] Institute for Cancer Research, Sutton, London, UK. [2] Northern Institute for Cancer Research, University of Newcastle, Newcastle-upon-Tyne, UK.
6
Centro Ricerca Tettamanti, Hospital San Gerardo, Monza, Italy.
7
Department of Paediatric Haematology and Oncology, 2nd Faculty of Medicine, Charles University Prague and University Hospital Motol, Prague, Czech Republic.
8
Paediatric Malignancy Unit, Molecular Haematology & Cancer Biology Unit, Camelia Botnar Laboratories, Great Ormond Street Hospital for Children and University College London (UCL) Institute of Child Health, London, UK.
9
Department of Laboratory Medicine, University of California, San Francisco, San Francisco, California, USA.
10
1] Institute for Cancer Research, Sutton, London, UK. [2].
11
1] Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK. [2] Addenbrooke's National Health Service (NHS) Foundation Trust, Cambridge, UK. [3] Department of Haematology, University of Cambridge, Cambridge, UK. [4].

Abstract

The ETV6-RUNX1 fusion gene, found in 25% of childhood acute lymphoblastic leukemia (ALL) cases, is acquired in utero but requires additional somatic mutations for overt leukemia. We used exome and low-coverage whole-genome sequencing to characterize secondary events associated with leukemic transformation. RAG-mediated deletions emerge as the dominant mutational process, characterized by recombination signal sequence motifs near breakpoints, incorporation of non-templated sequence at junctions, ∼30-fold enrichment at promoters and enhancers of genes actively transcribed in B cell development and an unexpectedly high ratio of recurrent to non-recurrent structural variants. Single-cell tracking shows that this mechanism is active throughout leukemic evolution, with evidence of localized clustering and reiterated deletions. Integration of data on point mutations and rearrangements identifies ATF7IP and MGA as two new tumor-suppressor genes in ALL. Thus, a remarkably parsimonious mutational process transforms ETV6-RUNX1-positive lymphoblasts, targeting the promoters, enhancers and first exons of genes that normally regulate B cell differentiation.

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PMID:
24413735
PMCID:
PMC3960636
DOI:
10.1038/ng.2874
[Indexed for MEDLINE]
Free PMC Article

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