title: Rise and fall of subclones from diagnosis to relapse in pediatric B-acute lymphoblastic leukaemia.
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.
authors: Computational Biology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors: Xiaotu
authors: X
authors: Ma
authors: Computational Biology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors: Michael
authors: M
authors: Edmonson
authors: Pediatric Cancer Genome Project Validation Lab, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors: Donald
authors: D
authors: Yergeau
authors: Cancer Genomics, Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 77030, USA.
authors: Donna M
authors: DM
authors: Muzny
authors: Cancer Genomics, Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 77030, USA.
authors: Oliver A
authors: OA
authors: Hampton
authors: Computational Biology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors: Michael
authors: M
authors: Rusch
authors: Pathology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors: Guangchun
authors: G
authors: Song
authors: Pediatric Cancer Genome Project Validation Lab, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors: John
authors: J
authors: Easton
authors: University of New Mexico Cancer Center, Albuquerque, New Mexico 87131, USA.
authors: Richard C
authors: RC
authors: Harvey
authors: Cancer Genomics, Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 77030, USA.
authors: David A
authors: DA
authors: Wheeler
authors: Pathology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors: Jing
authors: J
authors: Ma
authors: Cancer Genomics, Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 77030, USA.
authors: HarshaVardhan
authors: H
authors: Doddapaneni
authors: Pediatric Cancer Genome Project Validation Lab, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors: Bhavin
authors: B
authors: Vadodaria
authors: Computational Biology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors: Gang
authors: 0000000216785864
authors: G
authors: Wu
authors: Computational Biology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors: Panduka
authors: P
authors: Nagahawatte
authors: Perlmutter Cancer Center, NYU Langone Medical Center, New York, NY 10016, USA.
authors: William L
authors: WL
authors: Carroll
authors: University of New Mexico Cancer Center, Albuquerque, New Mexico 87131, USA.
authors: I-Ming
authors: IM
authors: Chen
authors: 1] Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, Ohio 43205, USA [2] Departments of Pathology and Pediatrics, The Ohio State University, Columbus, Ohio 43210, USA.
authors: Julie M
authors: JM
authors: Gastier-Foster
authors: Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors: Mary V
authors: MV
authors: Relling
authors: Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, Maryland 20892, USA.
authors: Malcolm A
authors: MA
authors: Smith
authors: Department of Biostatistics, Colleges of Medicine, Public Health &Health Professions, University of Florida, Gainesville, Florida 32607, USA.
authors: Meenakshi
authors: M
authors: Devidas
authors: Office of Cancer Genomics, National Cancer Institute, Bethesda, Maryland 20892, USA.
authors: Jaime M
authors: JM
authors: Guidry Auvil
authors: Pathology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors: James R
authors: JR
authors: Downing
authors: Department of Pediatrics, Benioff Children's Hospital and the Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California 94143, USA.
authors: Mignon L
authors: ML
authors: Loh
authors: University of New Mexico Cancer Center, Albuquerque, New Mexico 87131, USA.
authors: Cheryl L
authors: CL
authors: Willman
authors: Office of Cancer Genomics, National Cancer Institute, Bethesda, Maryland 20892, USA.
authors: Daniela S
authors: DS
authors: Gerhard
authors: Pathology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors: Charles G
authors: 0000000218711850
authors: CG
authors: Mullighan
authors: Division of Oncology and The Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
authors: Stephen P
authors: SP
authors: Hunger
authors: Computational Biology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors: Jinghui
authors: J
authors: Zhang
mesh_terms: D015720:5'-Nucleotidase / Q000235:genetics; D050882:CREB-Binding Protein / Q000235:genetics; D002648:Child; D060965:Clonal Evolution / Q000235:genetics*; D002999:Clone Cells; D056915:DNA Copy Number Variations; D018450:Disease Progression; D059472:Exome; D016326:Extracellular Matrix Proteins / Q000235:genetics; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics; D006801:Humans; D051740:Ikaros Transcription Factor / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D009154:Mutation; D009364:Neoplasm Recurrence, Local / Q000235:genetics*; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D016326:Extracellular Matrix Proteins; C497239:IKZF1 protein, human; D008565:Membrane Proteins; D012097:Repressor Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C112735:USH2A protein, human; D051740:Ikaros Transcription Factor; D011495:Histone-Lysine N-Methyltransferase; C419586:NSD2 protein, human; D050882:CREB-Binding Protein; C494363:CREBBP protein, human; D015720:5'-Nucleotidase; C508048:NT5C2 protein, human; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human