title: RAG-mediated recombination is the predominant driver of oncogenic rearrangement in ETV6-RUNX1 acute lymphoblastic leukemia.
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.
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK.
authors.forename: Elli
authors.initials: E
authors.lastname: Papaemmanuil
authors.affiliation: Hospital Universitario 12 de Octubre, Madrid, Spain.
authors.forename: Inmaculada
authors.initials: I
authors.lastname: Rapado
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK.
authors.forename: Yilong
authors.initials: Y
authors.lastname: Li
authors.affiliation: Institute for Cancer Research, Sutton, London, UK.
authors.forename: Nicola E
authors.initials: NE
authors.lastname: Potter
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK.
authors.forename: David C
authors.initials: DC
authors.lastname: Wedge
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK.
authors.forename: Jose
authors.initials: J
authors.lastname: Tubio
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK.
authors.forename: Ludmil B
authors.identifier: 0000000335964515
authors.initials: LB
authors.lastname: Alexandrov
authors.affiliation: 1] Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK. [2] Department of Human Genetics, VIB and University of Leuven, Leuven, Belgium.
authors.forename: Peter
authors.identifier: 0000000302921949
authors.initials: P
authors.lastname: Van Loo
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK.
authors.forename: Susanna L
authors.initials: SL
authors.lastname: Cooke
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK.
authors.forename: John
authors.initials: J
authors.lastname: Marshall
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK.
authors.forename: Inigo
authors.initials: I
authors.lastname: Martincorena
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Hinton
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK.
authors.forename: Gunes
authors.initials: G
authors.lastname: Gundem
authors.affiliation: 1] Institute for Cancer Research, Sutton, London, UK. [2] Northern Institute for Cancer Research, University of Newcastle, Newcastle-upon-Tyne, UK.
authors.forename: Frederik W
authors.initials: FW
authors.lastname: van Delft
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK.
authors.forename: Serena
authors.initials: S
authors.lastname: Nik-Zainal
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK.
authors.forename: David R
authors.initials: DR
authors.lastname: Jones
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK.
authors.forename: Manasa
authors.initials: M
authors.lastname: Ramakrishna
authors.affiliation: Institute for Cancer Research, Sutton, London, UK.
authors.forename: Ian
authors.initials: I
authors.lastname: Titley
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK.
authors.forename: Lucy
authors.initials: L
authors.lastname: Stebbings
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK.
authors.forename: Catherine
authors.initials: C
authors.lastname: Leroy
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Menzies
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK.
authors.forename: John
authors.initials: J
authors.lastname: Gamble
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: Laura
authors.initials: L
authors.lastname: Mudie
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK.
authors.forename: Keiran
authors.initials: K
authors.lastname: Raine
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: O'Meara
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK.
authors.forename: Jon W
authors.initials: JW
authors.lastname: Teague
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK.
authors.forename: Adam P
authors.initials: AP
authors.lastname: Butler
authors.affiliation: Centro Ricerca Tettamanti, Hospital San Gerardo, Monza, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Cazzaniga
authors.affiliation: Centro Ricerca Tettamanti, Hospital San Gerardo, Monza, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Biondi
authors.affiliation: Department of Paediatric Haematology and Oncology, 2nd Faculty of Medicine, Charles University Prague and University Hospital Motol, Prague, Czech Republic.
authors.forename: Jan
authors.initials: J
authors.lastname: Zuna
authors.affiliation: 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.
authors.forename: Helena
authors.initials: H
authors.lastname: Kempski
authors.affiliation: Department of Laboratory Medicine, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Markus
authors.initials: M
authors.lastname: Muschen
authors.affiliation: Institute for Cancer Research, Sutton, London, UK.
authors.forename: Anthony M
authors.initials: AM
authors.lastname: Ford
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Stratton
authors.affiliation: 1] Institute for Cancer Research, Sutton, London, UK. [2].
authors.forename: Mel
authors.initials: M
authors.lastname: Greaves
authors.affiliation: 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].
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Campbell
mesh_terms: D001483:Base Sequence; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics*; D056915:DNA Copy Number Variations / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D015723:Gene Library; D015321:Gene Rearrangement / Q000235:genetics*; D016147:Genes, Tumor Suppressor; D014644:Genetic Variation; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D008969:Molecular Sequence Data; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*; D011995:Recombination, Genetic / Q000235:genetics*; D012097:Repressor Proteins; D017422:Sequence Analysis, DNA; D017384:Sequence Deletion / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D060152:V(D)J Recombination / Q000235:genetics; D000097764:ETS Translocation Variant 6 Protein
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D050676:Core Binding Factor Alpha 2 Subunit; D018398:Homeodomain Proteins; D015514:Oncogene Proteins, Fusion; D012097:Repressor Proteins; D014157:Transcription Factors; C501309:ATF7IP protein, human; C584050:MGA protein, human; C102421:TEL-AML1 fusion protein; D000097764:ETS Translocation Variant 6 Protein; C064658:RAG-1 protein