title: High-resolution genomic profiling of childhood ALL reveals novel recurrent genetic lesions affecting pathways involved in lymphocyte differentiation and cell cycle progression.
abstract: Gross cytogenetic anomalies are traditionally being used as diagnostic, prognostic and therapeutic markers in the clinical management of cancer, including childhood acute lymphoblastic leukemia (ALL). Recently, it has become increasingly clear that genetic lesions driving tumorigenesis frequently occur at the submicroscopic level and, consequently, escape standard cytogenetic observations. Therefore, we profiled the genomes of 40 childhood ALLs at high resolution. We detected multiple de novo genetic lesions, including gross aneuploidies and segmental gains and losses, some of which were subtle and affected single genes. Many of these lesions involved recurrent (partially) overlapping deletions and duplications, containing various established leukemia-associated genes, such as ETV6, RUNX1 and MLL. Importantly, the most frequently affected genes were those controlling G1/S cell cycle progression (e.g. CDKN2A, CDKN1B and RB1), followed by genes associated with B-cell development. The latter group includes microdeletions of the B-lineage transcription factors PAX5, EBF, E2-2 and IKZF1 (Ikaros), as well as genes with other established roles in B-cell development, that is RAG1 and RAG2, FYN, PBEF1 or CBP/PAG. The fact that we frequently encountered multiple lesions affecting genes involved in cell cycle regulation and B-cell differentiation strongly suggests that both these processes need to be targeted independently and simultaneously to trigger ALL development.
authors: 1Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors: R P
authors: RP
authors: Kuiper
authors: E F P M
authors: EF
authors: Schoenmakers
authors: S V
authors: SV
authors: van Reijmersdal
authors: J Y
authors: JY
authors: Hehir-Kwa
authors: A Geurts
authors: AG
authors: van Kessel
authors: F N
authors: FN
authors: van Leeuwen
authors: P M
authors: PM
authors: Hoogerbrugge
mesh_terms: D001402:B-Lymphocytes / Q000166:cytology; D002453:Cell Cycle / Q000235:genetics*; D002454:Cell Differentiation / Q000235:genetics*; D002869:Chromosome Aberrations; D005260:Female; D018628:Gene Dosage; D020869:Gene Expression Profiling / Q000379:methods; D052138:Genes, Neoplasm; D023281:Genomics / Q000379:methods; D006801:Humans; D008214:Lymphocytes / Q000166:cytology*; D008297:Male; D009693:Nucleic Acid Hybridization; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000209:etiology / Q000235:genetics*; D014157:Transcription Factors
chemical_list: D014157:Transcription Factors