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Nat Commun. 2015 Mar 19;6:6604. doi: 10.1038/ncomms7604.

Rise and fall of subclones from diagnosis to relapse in pediatric B-acute lymphoblastic leukaemia.

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Computational Biology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Pediatric Cancer Genome Project Validation Lab, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Cancer Genomics, Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 77030, USA.
Pathology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
University of New Mexico Cancer Center, Albuquerque, New Mexico 87131, USA.
Perlmutter Cancer Center, NYU Langone Medical Center, New York, NY 10016, USA.
1] Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, Ohio 43205, USA [2] Departments of Pathology and Pediatrics, The Ohio State University, Columbus, Ohio 43210, USA.
Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, Maryland 20892, USA.
Department of Biostatistics, Colleges of Medicine, Public Health &Health Professions, University of Florida, Gainesville, Florida 32607, USA.
Office of Cancer Genomics, National Cancer Institute, Bethesda, Maryland 20892, USA.
Department of Pediatrics, Benioff Children's Hospital and the Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California 94143, USA.
Division of Oncology and The Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.


There is incomplete understanding of genetic heterogeneity and clonal evolution during cancer progression. Here we use deep whole-exome sequencing to describe the clonal architecture and evolution of 20 pediatric B-acute lymphoblastic leukaemias from diagnosis to relapse. We show that clonal diversity is comparable at diagnosis and relapse and clonal survival from diagnosis to relapse is not associated with mutation burden. Six pathways were frequently mutated, with NT5C2, CREBBP, WHSC1, TP53, USH2A, NRAS and IKZF1 mutations enriched at relapse. Half of the leukaemias had multiple subclonal mutations in a pathway or gene at diagnosis, but mostly with only one, usually minor clone, surviving therapy to acquire additional mutations and become the relapse founder clone. Relapse-specific mutations in NT5C2 were found in nine cases, with mutations in four cases being in descendants of the relapse founder clone. These results provide important insights into the genetic basis of treatment failure in ALL and have implications for the early detection of mutations driving relapse.

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