Browse by author
Lookup NU author(s): Dr Frederik van DelftORCiD
Full text for this publication is not currently held within this repository. Alternative links are provided below where available.
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, similar to 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.
Author(s): Papaemmanuil E, Rapado I, Li YL, Potter NE, Wedge DC, Tubio J, Alexandrov LB, Van Loo P, Cooke SL, Marshall J, Martincorena I, Hinton J, Gundem G, van Delft FW, Nik-Zainal S, Jones DR, Ramakrishna M, Titley I, Stebbings L, Leroy C, Menzies A, Gamble J, Robinson B, Mudie L, Raine K, O'Meara S, Teague JW, Butler AP, Cazzaniga G, Biondi A, Zuna J, Kempski H, Muschen M, Ford AM, Stratton MR, Greaves M, Campbell PJ
Publication type: Article
Publication status: Published
Journal: Nature Genetics
Year: 2014
Volume: 46
Issue: 2
Pages: 116-125
Print publication date: 12/01/2014
ISSN (print): 1061-4036
ISSN (electronic): 1546-1718
Publisher: Nature Publishing Group
URL: http://dx.doi.org/10.1038/ng.2874
DOI: 10.1038/ng.2874
Altmetrics provided by Altmetric