| Literature DB >> 24413735 |
Elli Papaemmanuil1, Inmaculada Rapado2, Yilong Li1, Nicola E Potter3, David C Wedge1, Jose Tubio1, Ludmil B Alexandrov1, Peter Van Loo4, Susanna L Cooke1, John Marshall1, Inigo Martincorena1, Jonathan Hinton1, Gunes Gundem1, Frederik W van Delft5, Serena Nik-Zainal1, David R Jones1, Manasa Ramakrishna1, Ian Titley3, Lucy Stebbings1, Catherine Leroy1, Andrew Menzies1, John Gamble1, Ben Robinson1, Laura Mudie1, Keiran Raine1, Sarah O'Meara1, Jon W Teague1, Adam P Butler1, Giovanni Cazzaniga6, Andrea Biondi6, Jan Zuna7, Helena Kempski8, Markus Muschen9, Anthony M Ford3, Michael R Stratton1, Mel Greaves10, Peter J Campbell11.
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.Entities:
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Year: 2014 PMID： 24413735 PMCID： PMC3960636 DOI： 10.1038/ng.2874
Source DB: PubMed Journal: Nat Genet ISSN： 1061-4036 Impact factor: 38.330