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. Smith, Meenakshi Devidas, Jaime M. Guidry Auvil, James R. Downing, Mignon L. Loh, Cheryl L. Willman, Daniela S. Gerhard, Charles G. Mullighan (), Stephen P. Hunger () and Jinghui Zhang ()
Additional contact information
Xiaotu Ma: Computational Biology, St Jude Children’s Research Hospital
Michael Edmonson: Computational Biology, St Jude Children’s Research Hospital
Donald Yergeau: Pediatric Cancer Genome Project Validation Lab, St Jude Children’s Research Hospital
Donna M. Muzny: Cancer Genomics, Human Genome Sequencing Center, Baylor College of Medicine
Oliver A. Hampton: Cancer Genomics, Human Genome Sequencing Center, Baylor College of Medicine
Michael Rusch: Computational Biology, St Jude Children’s Research Hospital
Guangchun Song: Pathology, St Jude Children’s Research Hospital
John Easton: Pediatric Cancer Genome Project Validation Lab, St Jude Children’s Research Hospital
Richard C. Harvey: University of New Mexico Cancer Center
David A. Wheeler: Cancer Genomics, Human Genome Sequencing Center, Baylor College of Medicine
Jing Ma: Pathology, St Jude Children’s Research Hospital
HarshaVardhan Doddapaneni: Cancer Genomics, Human Genome Sequencing Center, Baylor College of Medicine
Bhavin Vadodaria: Pediatric Cancer Genome Project Validation Lab, St Jude Children’s Research Hospital
Gang Wu: Computational Biology, St Jude Children’s Research Hospital
Panduka Nagahawatte: Computational Biology, St Jude Children’s Research Hospital
William L. Carroll: Perlmutter Cancer Center, NYU Langone Medical Center
I-Ming Chen: University of New Mexico Cancer Center
Julie M. Gastier-Foster: Nationwide Children's Hospital
Mary V. Relling: St Jude Children’s Research Hospital
Malcolm A. Smith: Cancer Therapy Evaluation Program, National Cancer Institute
Meenakshi Devidas: Colleges of Medicine, Public Health & Health Professions, University of Florida
Jaime M. Guidry Auvil: Office of Cancer Genomics, National Cancer Institute
James R. Downing: Pathology, St Jude Children’s Research Hospital
Mignon L. Loh: Benioff Children’s Hospital and the Helen Diller Family Comprehensive Cancer Center, University of California San Francisco
Cheryl L. Willman: University of New Mexico Cancer Center
Daniela S. Gerhard: Office of Cancer Genomics, National Cancer Institute
Charles G. Mullighan: Pathology, St Jude Children’s Research Hospital
Stephen P. Hunger: Children’s Hospital of Philadelphia
Jinghui Zhang: Computational Biology, St Jude Children’s Research Hospital

Nature Communications, 2015, vol. 6, issue 1, 1-12

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms7604

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