Abstract 509: Genomic profiling of acute lymphoblastic leukemia in ataxia telangiectasia patients reveals tight link between ATM mutations and chromothripsis

Recent developments in sequencing technologies lead to the discovery of a novel form of genome instability, termed chromothripsis. This catastrophic genomic event, involved in cancer formation, is characterized by tens to hundreds of locally clustered rearrangements on one chromosome, acquired simultaneously. We hypothesized that leukemias developing in individuals with Ataxia Telangiectasia, who are born with two mutated copies of the ATM gene, essential guardian of genome stability, would show a higher prevalence for chromothripsis due to the 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) in patients with Ataxia Telangiectasia. We detected a high frequency of chromothriptic events in these tumors, specifically on acrocentric chromosomes, as compared to tumors from individuals with other types of DNA repair syndromes (27 cases in total, of which 10 with Ataxia Telangiectasia). Our data show 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 are linked with frequent chromotripsis. Additionally, we show that ATM loss is associated with increased chromothripsis prevalence in further tumor entities. Citation Format: Manasi Ratnaparkhe, Mario Hlevnjak, Thorsten Kolb, Anna Jauch, Kendra Maass, Frauke Devens, Agata Rode, Volker Hovestadt, Andrey Korshunov, Agata Pastorczak, Wojciech Mlynarski, Stephanie Sungalee, Jan Korbel, Jessica Hoell, Ute Fischer, Till Milde, Christof Kramm, Michaela Nathrath, Krystyna Chrzanowska, Eugen Tausch, Masatoshi Takagi, Takashi Taga, Shlomi Constantini, Jan Loeffen, Jules Meijerink, Stefan Zielen, Gudrun Goehring, Brigitte Schlegelberger, Eberhard Maass, Reiner Siebert, Joachim Kunz, Andreas Kulozik, Barbara Worst, David Jones, Stefan Pfister, Marc Zapatka, Peter Lichter, Aurelie Ernst. Genomic profiling of acute lymphoblastic leukemia in ataxia telangiectasia patients reveals tight link between ATM mutations and chromothripsis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 509. doi:10.1158/1538-7445.AM2017-509