title: The mutational landscape in pediatric acute lymphoblastic leukemia deciphered by whole genome sequencing.
abstract: Genomic characterization of pediatric acute lymphoblastic leukemia (ALL) has identified distinct patterns of genes and pathways altered in patients with well-defined genetic aberrations. To extend the spectrum of known somatic variants in ALL, we performed whole genome and transcriptome sequencing of three B-cell precursor patients, of which one carried the t(12;21)ETV6-RUNX1 translocation and two lacked a known primary genetic aberration, and one T-ALL patient. We found that each patient had a unique genome, with a combination of well-known and previously undetected genomic aberrations. By targeted sequencing in 168 patients, we identified KMT2D and KIF1B as novel putative driver genes. We also identified a putative regulatory non-coding variant that coincided with overexpression of the growth factor MDK. Our results contribute to an increased understanding of the biological mechanisms that lead to ALL and suggest that regulatory variants may be more important for cancer development than recognized to date. The heterogeneity of the genetic aberrations in ALL renders whole genome sequencing particularly well suited for analysis of somatic variants in both research and diagnostic applications.
authors.affiliation: Department of Medical Sciences, Molecular Medicine and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Carl Mårten
authors.initials: CM
authors.lastname: Lindqvist
authors.forename: Jessica
authors.initials: J
authors.lastname: Nordlund
authors.forename: Diana
authors.initials: D
authors.lastname: Ekman
authors.forename: Anna
authors.initials: A
authors.lastname: Johansson
authors.forename: Behrooz Torabi
authors.initials: BT
authors.lastname: Moghadam
authors.forename: Amanda
authors.initials: A
authors.lastname: Raine
authors.forename: Elin
authors.initials: E
authors.lastname: Övernäs
authors.forename: Johan
authors.initials: J
authors.lastname: Dahlberg
authors.forename: Per
authors.initials: P
authors.lastname: Wahlberg
authors.forename: Niklas
authors.initials: N
authors.lastname: Henriksson
authors.forename: Jonas
authors.initials: J
authors.lastname: Abrahamsson
authors.forename: Britt-Marie
authors.initials: BM
authors.lastname: Frost
authors.forename: Dan
authors.initials: D
authors.lastname: Grandér
authors.forename: Mats
authors.initials: M
authors.lastname: Heyman
authors.forename: Rolf
authors.initials: R
authors.lastname: Larsson
authors.forename: Josefine
authors.initials: J
authors.lastname: Palle
authors.forename: Stefan
authors.initials: S
authors.lastname: Söderhäll
authors.forename: Erik
authors.initials: E
authors.lastname: Forestier
authors.forename: Gudmar
authors.initials: G
authors.lastname: Lönnerholm
authors.forename: Ann-Christine
authors.initials: AC
authors.lastname: Syvänen
authors.forename: Eva C
authors.initials: EC
authors.lastname: Berglund
mesh_terms: D002648:Child; D002675:Child, Preschool; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D015894:Genome, Human; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D007223:Infant; D016547:Kinesins / Q000235:genetics*; D008297:Male; D000078792:Midkine; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics*; D009414:Nerve Growth Factors / Q000235:genetics*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*; D017422:Sequence Analysis, DNA / Q000379:methods; D017423:Sequence Analysis, RNA / Q000379:methods
chemical_list: D004268:DNA-Binding Proteins; C091053:KIF1B protein, human; C120898:KMT2D protein, human; C066254:MDK protein, human; D009363:Neoplasm Proteins; D009414:Nerve Growth Factors; D000078792:Midkine; D016547:Kinesins
keywords: RNA sequencing; acute lymphoblastic leukemia; clonal heterogeneity; whole genome sequencing