Title | Rise and fall of subclones from diagnosis to relapse in pediatric B-acute lymphoblastic leukaemia. |
Publication Type | Journal Article |
Year of Publication | 2015 |
Authors | Ma, X, Edmonson, M, Yergeau, D, Muzny, DM, Hampton, OA, Rusch, M, Song, G, Easton, J, Harvey, RC, Wheeler, DA, Ma, J, Doddapaneni, H, Vadodaria, B, Wu, G, Nagahawatte, P, Carroll, WL, Chen, I-M, Gastier-Foster, JM, Relling, MV, Smith, MA, Devidas, M, Auvil, JMGuidry, Downing, JR, Loh, ML, Willman, CL, Gerhard, DS, Mullighan, CG, Hunger, SP, Zhang, J |
Journal | Nat Commun |
Volume | 6 |
Pagination | 6604 |
Date Published | 2015 Mar 19 |
ISSN | 2041-1723 |
Keywords | 5'-Nucleotidase, Child, Clonal Evolution, Clone Cells, CREB-Binding Protein, Disease Progression, DNA Copy Number Variations, Exome, Extracellular Matrix Proteins, Female, GTP Phosphohydrolases, Histone-Lysine N-Methyltransferase, Humans, Ikaros Transcription Factor, Male, Membrane Proteins, Mutation, Neoplasm Recurrence, Local, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma, Repressor Proteins, Tumor Suppressor Protein p53 |
Abstract | 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. |
DOI | 10.1038/ncomms7604 |
Alternate Journal | Nat Commun |
PubMed ID | 25790293 |
PubMed Central ID | PMC4377644 |
Grant List | GM92666 / GM / NIGMS NIH HHS / United States U10 CA98413 / CA / NCI NIH HHS / United States HHSN261200800001C / CA / NCI NIH HHS / United States P30 CA021765 / CA / NCI NIH HHS / United States HHSN261200800001E / CA / NCI NIH HHS / United States U01 CA157937 / CA / NCI NIH HHS / United States U10 CA098543 / CA / NCI NIH HHS / United States U10 CA180886 / CA / NCI NIH HHS / United States U01 GM092666 / GM / NIGMS NIH HHS / United States U10 CA098413 / CA / NCI NIH HHS / United States U24 CA114766 / CA / NCI NIH HHS / United States CA21765 / CA / NCI NIH HHS / United States R01 CA161202 / CA / NCI NIH HHS / United States HHSN261200800001E / CA / NCI NIH HHS / United States U10 CA98543 / CA / NCI NIH HHS / United States |
Rise and fall of subclones from diagnosis to relapse in pediatric B-acute lymphoblastic leukaemia.
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