title: Whole-exome sequencing of pediatric acute lymphoblastic leukemia.
abstract: Acute lymphoblastic leukemia (ALL), the most common malignant disorder in childhood, is typically associated with numerical chromosomal aberrations, fusion genes or small focal deletions, thought to represent important pathogenetic events in the development of the leukemia. Mutations, such as single nucleotide changes, have also been reported in childhood ALL, but these have only been studied by sequencing a small number of candidate genes. Herein, we report the first unbiased sequencing of the whole exome of two cases of pediatric ALL carrying the ETV6/RUNX1 (TEL/AML1) fusion gene (the most common genetic subtype) and corresponding normal samples. A total of 14 somatic mutations were identified, including four and seven protein-altering nucleotide substitutions in each ALL. Twelve mutations (86%) occurred in genes previously described to be mutated in other types of cancer, but none was found to be recurrent in an extended series of 29 ETV6/RUNX1-positive ALLs. The number of single nucleotide mutations was similar to the number of copy number alterations as detected by single nucleotide polymorphism arrays. Although the true pathogenetic significance of the mutations must await future functional evaluations, this study provides a first estimate of the mutational burden at the genetic level of t(12;21)-positive childhood ALL.
authors.affiliation: Department of Clinical Genetics, University and Regional Laboratories, Skåne University Hospital, Lund University, Lund, Sweden. henrik.lilljebjorn@med.lu.se
authors.forename: H
authors.initials: H
authors.lastname: Lilljebjörn
authors.forename: M
authors.initials: M
authors.lastname: Rissler
authors.forename: C
authors.initials: C
authors.lastname: Lassen
authors.forename: J
authors.initials: J
authors.lastname: Heldrup
authors.forename: M
authors.initials: M
authors.lastname: Behrendtz
authors.forename: F
authors.initials: F
authors.lastname: Mitelman
authors.forename: B
authors.initials: B
authors.lastname: Johansson
authors.forename: T
authors.initials: T
authors.lastname: Fioretos
mesh_terms: D016022:Case-Control Studies; D002648:Child; D002869:Chromosome Aberrations; D050676:Core Binding Factor Alpha 2 Subunit; D059472:Exome / Q000235:genetics*; D018628:Gene Dosage; D050939:Gene Fusion; D006801:Humans; D009154:Mutation / Q000235:genetics*; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*; D011379:Prognosis; D017422:Sequence Analysis, DNA; D000097764:ETS Translocation Variant 6 Protein
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; D015514:Oncogene Proteins, Fusion; C102421:TEL-AML1 fusion protein; D000097764:ETS Translocation Variant 6 Protein