Rise and fall of subclones from diagnosis to relapse in pediatric B-acute lymphoblastic leukaemia
Date
2015
Authors
Ma, X.
Edmonson, M.
Yergeau, D.
Muzny, D.
Hampton, O.
Rusch, M.
Song, G.
Easton, J.
Harvey, R.
Wheeler, D.
Editors
Advisors
Journal Title
Journal ISSN
Volume Title
Type:
Journal article
Citation
Nature Communications, 2015; 6(1):6604-1-6604-12
Statement of Responsibility
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
Conference Name
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.
School/Discipline
Dissertation Note
Provenance
Description
Access Status
Rights
© 2015 Macmillan Publishers Limited. All rights reserved.