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

TitleRise and fall of subclones from diagnosis to relapse in pediatric B-acute lymphoblastic leukaemia.
Publication TypeJournal Article
Year of Publication2015
AuthorsMa, X, Edmonson, M, Yergeau, D, Muzny, DM, Hampton, OA, Rusch, M, Song, G, Easton, J, Harvey, RC, Wheeler, DA, Ma, J, Doddapaneni, HV, 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
JournalNat Commun
Volume6
Pagination6604
Date Published2015 Mar 19
ISSN2041-1723
Keywords5'-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.

DOI10.1038/ncomms7604
Alternate JournalNat Commun
PubMed ID25790293
PubMed Central IDPMC4377644
Grant ListGM92666 / GM / NIGMS NIH HHS / United States
U10 CA98413 / CA / NCI 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
P30 CA021765 / CA / NCI NIH HHS / United States
HHSN261200800001E / / PHS HHS / United States
U01 CA157937 / CA / NCI NIH HHS / United States
HHSN261200800001 / RC / CCR NIH HHS / United States
U10 CA098543 / CA / NCI NIH HHS / United States
U10 CA180886 / CA / NCI NIH HHS / United States
HHSN261200800001E / CA / NCI NIH HHS / United States
U10 CA98543 / CA / NCI NIH HHS / United States
U01 GM092666 / GM / NIGMS NIH HHS / United States