Genomic profiling of Acute lymphoblastic leukemia in ataxia telangiectasia patients reveals tight link between ATM mutations and chromothripsis

• Published in: Leukemia 2017-10, Vol.31 (10), p.2048-2056
• Main Authors: Ratnaparkhe, M, Hlevnjak, M, Kolb, T, Jauch, A, Maass, K K, Devens, F, Rode, A, Hovestadt, V, Korshunov, A, Pastorczak, A, Mlynarski, W, Sungalee, S, Korbel, J, Hoell, J, Fischer, U, Milde, T, Kramm, C, Nathrath, M, Chrzanowska, K, Tausch, E, Takagi, M, Taga, T, Constantini, S, Loeffen, J, Meijerink, J, Zielen, S, Gohring, G, Schlegelberger, B, Maass, E, Siebert, R, Kunz, J, Kulozik, A E, Worst, B, Jones, D T, Pfister, S M, Zapatka, M, Lichter, P, Ernst, A
• Format: Article
• Language: English
• Subjects: 14/32; 45/91; 631/208/69; 631/67/1990/283; Acute lymphoblastic leukemia; Acute lymphocytic leukemia; Adolescent; Ataxia; Ataxia telangiectasia; Ataxia Telangiectasia - complications; Ataxia Telangiectasia - genetics; Ataxia telangiectasia mutated protein; Ataxia Telangiectasia Mutated Proteins - deficiency; Ataxia Telangiectasia Mutated Proteins - genetics; Ataxia Telangiectasia Mutated Proteins - physiology; Cancer Research; Catastrophic events; Child; Child, Preschool; Chromosomes; Chromosomes, Human - ultrastructure; Chromothripsis; Critical Care Medicine; Deoxyribonucleic acid; Development and progression; DNA; DNA damage; DNA repair; DNA Repair - genetics; DNA sequencing; DNA, Neoplasm - genetics; Double-strand break repair; Female; Fluorescence; Fluorescence in situ hybridization; Gene mutation; Genetic aspects; Genome, Human; Genomes; Genomic Instability; Hematology; Humans; In Situ Hybridization, Fluorescence; Intensive; Internal Medicine; Leukemia; Lymphatic leukemia; Male; Medicine; Medicine & Public Health; Mutation; Neoplasm Proteins - deficiency; Neoplasm Proteins - genetics; Neoplasm Proteins - physiology; Neoplasms - genetics; Oncology; original-article; Patients; Precursor Cell Lymphoblastic Leukemia-Lymphoma - etiology; Precursor Cell Lymphoblastic Leukemia-Lymphoma - genetics; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - genetics; Repair; Ribonucleic acid; RNA; RNA, Neoplasm - genetics; Sequence Analysis, DNA; Sequence Analysis, RNA; Stability; Telomere Shortening - genetics; Telomeres; Transcriptome; Tumorigenesis; Tumors; Whole genome sequencing
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/leu.2017.55

Recent developments in sequencing technologies led to the discovery of a novel form of genomic instability, termed chromothripsis. This catastrophic genomic event, involved in tumorigenesis, is characterized by tens to hundreds of simultaneously acquired locally clustered rearrangements on one chromosome. We hypothesized that leukemias developing in individuals with Ataxia Telangiectasia, who are born with two mutated copies of the ATM gene, an essential guardian of genome stability, would show a higher prevalence of chromothripsis due to the associated defect in DNA double-strand break repair. Using whole-genome sequencing, fluorescence in situ hybridization and RNA sequencing, we characterized the genomic landscape of Acute Lymphoblastic Leukemia (ALL) arising in patients with Ataxia Telangiectasia. We detected a high frequency of chromothriptic events in these tumors, specifically on acrocentric chromosomes, as compared with tumors from individuals with other types of DNA repair syndromes (27 cases total, 10 with Ataxia Telangiectasia). Our data suggest that the genomic landscape of Ataxia Telangiectasia ALL is clearly distinct from that of sporadic ALL. Mechanistically, short telomeres and compromised DNA damage response in cells of Ataxia Telangiectasia patients may be linked with frequent chromothripsis. Furthermore, we show that ATM loss is associated with increased chromothripsis prevalence in additional tumor entities.