Abstract
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.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Stephens PJ, Greenman CD, Fu B, Yang F, Bignell GR, Mudie LJ et al. Massive genomic rearrangement acquired in a single catastrophic event during cancer development. Cell 2011; 144: 27–40.
Rausch T, Jones DT, Zapatka M, Stutz AM, Zichner T, Weischenfeldt J et al. Genome sequencing of pediatric medulloblastoma links catastrophic DNA rearrangements with TP53 mutations. Cell 2012; 148: 59–71.
Korbel JO, Campbell PJ . Criteria for inference of chromothripsis in cancer genomes. Cell 2013; 152: 1226–1236.
Rode A, Maass KK, Willmund KV, Lichter P, Ernst A . Chromothripsis in cancer cells, an update. Int J Cancer 2015; 138: 2322–2333.
Li Y, Schwab C, Ryan SL, Papaemmanuil E, Robinson HM, Jacobs P et al. Constitutional and somatic rearrangement of chromosome 21 in acute lymphoblastic leukaemia. Nature 2014; 508: 98–102.
Parker H, Rose-Zerilli MJ, Larrayoz M, Clifford R, Edelmann J, Blakemore S et al. Genomic disruption of the histone methyltransferase SETD2 in chronic lymphocytic leukaemia. Leukemia 2016; 30: 2179–2186.
Kastan MB, Lim DS . The many substrates and functions of ATM. Nat Rev Mol Cell Biol 2000; 1: 179–186.
Oxford JM, Harnden DG, Parrington JM, Delhanty JD . Specific chromosome aberrations in ataxia telangiectasia. J Med Genet 1975; 12: 251–262.
Morrell D, Cromartie E, Swift M . Mortality and cancer incidence in 263 patients with ataxia-telangiectasia. J Natl Cancer Inst 1986; 77: 89–92.
Taylor AM, Metcalfe JA, Thick J, Mak YF . Leukemia and lymphoma in ataxia telangiectasia. Blood 1996; 87: 423–438.
Zhang J, Ding L, Holmfeldt L, Wu G, Heatley SL, Payne-Turner D et al. The genetic basis of early T-cell precursor acute lymphoblastic leukaemia. Nature 2012; 481: 157–163.
Zack TI, Schumacher SE, Carter SL, Cherniack AD, Saksena G, Tabak B et al. Pan-cancer patterns of somatic copy number alteration. Nat Genet 2013; 45: 1134–1140.
Crasta K, Ganem NJ, Dagher R, Lantermann AB, Ivanova EV, Pan Y et al. DNA breaks and chromosome pulverization from errors in mitosis. Nature 2012; 482: 53–58.
Zhang CZ, Spektor A, Cornils H, Francis JM, Jackson EK, Liu S et al. Chromothripsis from DNA damage in micronuclei. Nature 2015; 522: 179–184.
Migliore L, Coppede F, Fenech M, Thomas P . Association of micronucleus frequency with neurodegenerative diseases. Mutagenesis 2011; 26: 85–92.
Remke M, Pfister S, Kox C, Toedt G, Becker N, Benner A et al. High-resolution genomic profiling of childhood T-ALL reveals frequent copy-number alterations affecting the TGF-beta and PI3K-AKT pathways and deletions at 6q15-16.1 as a genomic marker for unfavorable early treatment response. Blood 2009; 114: 1053–1062.
Lantelme E, Turinetto V, Mantovani S, Marchi A, Regazzoni S, Porcedda P et al. Analysis of secondary V(D)J rearrangements in mature, peripheral T cells of ataxia-telangiectasia heterozygotes. Lab Investig: J Tech Methods Pathol 2003; 83: 1467–1475.
Lantelme E, Mantovani S, Palermo B, Campanelli R, Granziero L, Monafo V et al. Increased frequency of RAG-expressing, CD4(+)CD3(low) peripheral T lymphocytes in patients with defective responses to DNA damage. Eur J Immunol 2000; 30: 1520–1525.
Papaemmanuil E, Rapado I, Li Y, Potter NE, Wedge DC, Tubio J et al. RAG-mediated recombination is the predominant driver of oncogenic rearrangement in ETV6-RUNX1 acute lymphoblastic leukemia. Nat Genet 2014; 46: 116–125.
Verhagen MM, Last JI, Hogervorst FB, Smeets DF, Roeleveld N, Verheijen F et al. Presence of ATM protein and residual kinase activity correlates with the phenotype in ataxia-telangiectasia: a genotype-phenotype study. Hum Mutat 2012; 33: 561–571.
van Belzen MJ, Hiel JA, Weemaes CM, Gabreels FJ, van Engelen BG, Smeets DF et al. A double missense mutation in the ATM gene of a Dutch family with ataxia telangiectasia. Hum Genetics 1998; 102: 187–191.
Maciejowski J, Li Y, Bosco N, Campbell PJ, de Lange T . Chromothripsis and Kataegis induced by telomere crisis. Cell 2015; 163: 1641–1654.
Ernst A, Jones DT, Maass KK, Rode A, Deeg KI, Michael Chelliah Jebaraj B et al. Telomere dysfunction and chromothripsis. Int J Cancer 2016; 138: 2905–2914.
Di Domenico EG, Romano E, Del Porto P, Ascenzioni F . Multifunctional role of ATM/Tel1 kinase in genome stability: from the DNA damage response to telomere maintenance. BioMed Res Int 2014; 2014: 787404.
Doksani Y, de Lange T . The role of double-strand break repair pathways at functional and dysfunctional telomeres. Cold Spring Harbor Perspect Biol 2014; 6: a016576.
Pandita TK . ATM function and telomere stability. Oncogene 2002; 21: 611–618.
Metcalfe JA, Parkhill J, Campbell L, Stacey M, Biggs P, Byrd PJ et al. Accelerated telomere shortening in ataxia telangiectasia. Nat Genet 1996; 13: 350–353.
Hu J, Tepsuporn S, Meyers RM, Gostissa M, Alt FW . Developmental propagation of V(D)J recombination-associated DNA breaks and translocations in mature B cells via dicentric chromosomes. Proc Natl Acad Sci USA 2014; 111: 10269–10274.
Conrad DF, Bird C, Blackburne B, Lindsay S, Mamanova L, Lee C et al. Mutation spectrum revealed by breakpoint sequencing of human germline CNVs. Nat Genet 2010; 42: 385–391.
Moreira F, Kiehl TR, So K, Ajeawung NF, Honculada C, Gould P et al. NPAS3 demonstrates features of a tumor suppressive role in driving the progression of Astrocytomas. Am J Pathol 2011; 179: 462–476.
Bao BY, Lin VC, Yu CC, Yin HL, Chang TY, Lu TL et al. Genetic variants in ultraconserved regions associate with prostate cancer recurrence and survival. Sci Rep 2016; 6: 22124.
Sun HT, Cheng SX, Tu Y, Li XH, Zhang S . FoxQ1 promotes glioma cells proliferation and migration by regulating NRXN3 expression. PLoS ONE 2013; 8: e55693.
Alexandrov LB, Nik-Zainal S, Wedge DC, Aparicio SA, Behjati S, Biankin AV et al. Signatures of mutational processes in human cancer. Nature 2013; 500: 415–421.
Edelmann J, Holzmann K, Miller F, Winkler D, Buhler A, Zenz T et al. High-resolution genomic profiling of chronic lymphocytic leukemia reveals new recurrent genomic alterations. Blood 2012; 120: 4783–4794.
Stimpson KM, Sullivan LL, Kuo ME, Sullivan BA . Nucleolar organization, ribosomal DNA array stability, and acrocentric chromosome integrity are linked to telomere function. PLoS ONE 2014; 9: e92432.
Shull ER, Lee Y, Nakane H, Stracker TH, Zhao J, Russell HR et al. Differential DNA damage signaling accounts for distinct neural apoptotic responses in ATLD and NBS. Genes Dev 2009; 23: 171–180.
Britt-Compton B, Lin TT, Ahmed G, Weston V, Jones RE, Fegan C et al. Extreme telomere erosion in ATM-mutated and 11q-deleted CLL patients is independent of disease stage. Leukemia 2012; 26: 826–830.
Acknowledgements
We are particularly grateful for the precious assistance of Michaela Hergt for immunofluorescence analyses, Achim Stephan for library preparation for RNA sequencing, Brigitte Schoell for M-FISH analyses, Mareike Doerrenberg for extraction of nucleic acids and David Westermann for TP53 sequencing. We would also like to express our deep gratitude to Angela Schulz, Nicolle Diessl, Laura-Jane Behl, Stephan Wolf from the Genomics & Proteomics Core Facility, DKFZ, and to Katja Beck for excellent support with the next-generation sequencing analyses. Roland Eils, Prakash Balasubramanian, Ivo Buchhalter, Daniel Hübschmann and Andreas Kloetgen are gratefully acknowledged for generous sharing of bioinformatic tools and/or help with data transfer, and Susanne Gröbner for kindly helping with mutational signature analyses. We also thank Polina Stepensky, Arndt Borkhardt, Olaf Witt and Stephan Stilgenbauer for their generous support for this study. We would like to express our special appreciation and thanks to Julia Hauer and Esmé Waanders for discussions, and to Martina Seiffert for comments on the manuscript. Finally, we would like to thank Michael Hain for excellent IT support, the DKFZ Light Microscopy Facility, and the Wilhelm Sander Stiftung for financial support.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Additional information
Supplementary Information accompanies this paper on the Leukemia website
Supplementary information
Rights and permissions
About this article
Cite this article
Ratnaparkhe, M., Hlevnjak, M., Kolb, T. et al. Genomic profiling of Acute lymphoblastic leukemia in ataxia telangiectasia patients reveals tight link between ATM mutations and chromothripsis. Leukemia 31, 2048–2056 (2017). https://doi.org/10.1038/leu.2017.55
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/leu.2017.55
- Springer Nature Limited
This article is cited by
-
Chromothripsis is a frequent event and underlies typical genetic changes in early T-cell precursor lymphoblastic leukemia in adults
Leukemia (2022)
-
Prevalence and mechanisms of somatic deletions in single human neurons during normal aging and in DNA repair disorders
Nature Communications (2022)
-
Involvement of classic and alternative non-homologous end joining pathways in hematologic malignancies: targeting strategies for treatment
Experimental Hematology & Oncology (2021)
-
Chitosan as possible inhibitory agents and delivery systems in leukemia
Cancer Cell International (2021)
-
ERα-related chromothripsis enhances concordant gene transcription on chromosome 17q11.1-q24.1 in luminal breast cancer
BMC Medical Genomics (2020)