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

Nature Communications
Xiaotu MaJinghui Zhang

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.

References

Sep 3, 2003·Nature Reviews. Cancer·Mel F Greaves, Joe Wiemels
Jul 8, 2008·Gastroenterology·Leigha SenterAlbert de la Chapelle
Nov 29, 2008·Science·Charles G MullighanJames R Downing
May 28, 2009·Proceedings of the National Academy of Sciences of the United States of America·Charles G MullighanCheryl L Willman
Jun 10, 2009·Bioinformatics·Heng LiUNKNOWN 1000 Genome Project Data Processing Subgroup
Oct 15, 2009·Hematology/oncology Clinics of North America·Dario Campana
Jan 19, 2010·Bioinformatics·Heng Li, Richard Durbin
Mar 11, 2011·Nature·Charles G MullighanJames R Downing
Mar 16, 2012·The New England Journal of Medicine·Matthew J WalterTimothy A Graubert
Feb 5, 2013·Nature Genetics·Julia A MeyerWilliam L Carroll
Sep 7, 2013·British Journal of Haematology·Andrew E PlaceStephen E Sallan

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Citations

Feb 10, 2016·Cancer Cell·Ilaria IacobucciCharles G Mullighan
Oct 13, 2015·Pediatrics International : Official Journal of the Japan Pediatric Society·Hiroaki Goto
Oct 16, 2015·The New England Journal of Medicine·Stephen P Hunger, Charles G Mullighan
Dec 9, 2015·Cell Systems·Malachi GriffithRichard K Wilson
May 26, 2016·British Journal of Haematology·Paul S Gaynon, Weili Sun
Jun 29, 2016·British Journal of Haematology·Peter HoklandMarcus C Hansen
Sep 23, 2016·Proceedings of the National Academy of Sciences of the United States of America·Koichi OshimaAdolfo A Ferrando
Sep 25, 2016·Proceedings of the National Academy of Sciences of the United States of America·Sydney X Lu, Omar Abdel-Wahab
Oct 18, 2016·Pediatric Blood & Cancer·Rajen J ModyArul M Chinnaiyan
Dec 23, 2016·Cold Spring Harbor Perspectives in Medicine·Evan Q Comeaux, Charles G Mullighan
Mar 16, 2017·European Journal of Immunology·Mario FidanzaGregor S D Reid
Jan 18, 2017·Journal of Molecular Medicine : Official Organ of the Gesellschaft Deutscher Naturforscher Und Ärzte·Rolando A R VillacisSilvia R Rogatto
May 5, 2017·Pharmacogenomics·Zeina N Al-MahayriBassam R Ali
Dec 4, 2016·Hematology·Thai Hoa Tran, Mignon L Loh
Dec 4, 2016·Hematology·Elizabeth A Raetz, David T Teachey
Jun 27, 2017·Expert Review of Anticancer Therapy·Joanna PierroWilliam L Carroll
Feb 27, 2018·Cell and Tissue Research·Marc SchulteAlexander Schramm
May 12, 2016·Leukemia·S L RyanC J Harrison
Nov 4, 2017·F1000Research·Jan Starý, Ondřej Hrušák
Aug 19, 2016·Nature Communications·Pierre HirschFrançois Delhommeau
Oct 27, 2018·Purinergic Signalling·Lars Petter Jordheim
Apr 11, 2018·Nature Medicine·José Ignacio Martín-Subero

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Methods Mentioned

BETA
electrophoresis
Chip
PCR

Software Mentioned

SeqCap
Bambino
Illumina CASAVA )
Nimbledesign
FusionBuilder
WXS
R package mclust
Mercury
HiSeq Real - time Analysis
dChip

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