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

Xiaotu Ma, Michael Edmonson, Donald Yergeau, Donna M. Muzny, Oliver A. Hampton, Michael Rusch, Guangchun Song, John Easton, Richard C. Harvey, David A. Wheeler, Jing Ma, Harshavardhan Doddapaneni, Bhavin Vadodaria, Gang Wu, Panduka Nagahawatte, William L. Carroll, I. Ming Chen, Julie M. Gastier-Foster, Mary V. Relling, Malcolm A. SmithMeenakshi Devidas, Jaime M.Guidry Auvil, James R. Downing, Mignon L. Loh, Cheryl L. Willman, Daniela S. Gerhard, Charles G. Mullighan, Stephen P. Hunger, Jinghui Zhang

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article number6604
JournalNature communications
Volume6
DOIs
StatePublished - Mar 19 2015

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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