Commonly altered genomic regions in acute myeloid leukemia are enriched for somatic mutations involved in chromatin remodeling and splicing

Blood - Tập 120 - Trang e83-e92 - 2012
Anna Dolnik1, Julia C. Engelmann2, Maren Scharfenberger-Schmeer3, Julian Mauch1, Sabine Kelkenberg-Schade3, Berit Haldemann3, Tamara Fries3, Jan Krönke1, Michael W.M. Kühn1, Peter Paschka1, Sabine Kayser1, Stephan Wolf3, Verena I. Gaidzik1, Richard F. Schlenk1, Frank G. Rücker1, Hartmut Döhner1, Claudio Lottaz2, Konstanze Döhner1, Lars Bullinger1
1Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany
2Statistical Bioinformatics, Institute for Functional Genomics, University of Regensburg, Regensburg, Germany
3Genomics and Proteomics Core Facilities, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany

Tóm tắt

Abstract Acute myeloid leukemia (AML) is characterized by molecular heterogeneity. As commonly altered genomic regions point to candidate genes involved in leukemogenesis, we used microarray-based comparative genomic hybridization and single nucleotide polymorphism profiling data of 391 AML cases to further narrow down genomic regions of interest. Targeted resequencing of 1000 genes located in the critical regions was performed in a representative cohort of 50 AML samples comprising all major cytogenetic subgroups. We identified 120 missense/nonsense mutations as well as 60 insertions/deletions affecting 73 different genes (∼ 3.6 tumor-specific aberrations/AML). While most of the newly identified alterations were nonrecurrent, we observed an enrichment of mutations affecting genes involved in epigenetic regulation including known candidates like TET2, TET1, DNMT3A, and DNMT1, as well as mutations in the histone methyltransferases NSD1, EZH2, and MLL3. Furthermore, we found mutations in the splicing factor SFPQ and in the nonclassic regulators of mRNA processing CTCF and RAD21. These splicing-related mutations affected 10% of AML patients in a mutually exclusive manner. In conclusion, we could identify a large number of alterations in genes involved in aberrant splicing and epigenetic regulation in genomic regions commonly altered in AML, highlighting their important role in the molecular pathogenesis of AML.

Tài liệu tham khảo

Dohner, 2010, Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet., Blood, 115, 453, 10.1182/blood-2009-07-235358 Ley, 2010, DNMT3A mutations in acute myeloid leukemia., N Engl J Med, 363, 2424, 10.1056/NEJMoa1005143 Ley, 2008, DNA sequencing of a cytogenetically normal acute myeloid leukaemia genome., Nature, 456, 66, 10.1038/nature07485 Link, 2011, Identification of a novel TP53 cancer susceptibility mutation through whole-genome sequencing of a patient with therapy-related AML., J Am Med Assoc, 305, 1568, 10.1001/jama.2011.473 Mardis, 2009, Recurring mutations found by sequencing an acute myeloid leukemia genome., N Engl J Med, 361, 1058, 10.1056/NEJMoa0903840 Yan, 2011, Exome sequencing identifies somatic mutations of DNA methyltransferase gene DNMT3A in acute monocytic leukemia., Nat Genet, 43, 309, 10.1038/ng.788 Paschka, 2010, IDH1 and IDH2 mutations are frequent genetic alterations in acute myeloid leukemia and confer adverse prognosis in cytogenetically normal acute myeloid leukemia with NPM1 mutation without FLT3 internal tandem duplication., J Clin Oncol, 28, 3636, 10.1200/JCO.2010.28.3762 Figueroa, 2010, Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation., Cancer Cell, 18, 553, 10.1016/j.ccr.2010.11.015 Papaemmanuil, 2011, Somatic SF3B1 mutation in myelodysplasia with ring sideroblasts., N Engl J Med, 365, 1384, 10.1056/NEJMoa1103283 Yoshida, 2011, Frequent pathway mutations of splicing machinery in myelodysplasia., Nature, 478, 64, 10.1038/nature10496 Morin, 2011, Frequent mutation of histone-modifying genes in non-Hodgkin lymphoma., Nature, 476, 298, 10.1038/nature10351 Pasqualucci, 2011, Analysis of the coding genome of diffuse large B-cell lymphoma., Nat Genet, 43, 830, 10.1038/ng.892 Ding, 2010, Genome remodelling in a basal-like breast cancer metastasis and xenograft., Nature, 464, 999, 10.1038/nature08989 Lee, 2010, The mutation spectrum revealed by paired genome sequences from a lung cancer patient., Nature, 465, 473, 10.1038/nature09004 Mullighan, 2009, Genome-wide profiling of genetic alterations in acute lymphoblastic leukemia: recent insights and future directions., Leukemia, 23, 1209, 10.1038/leu.2009.18 Bullinger, 2010, Identification of acquired copy number alterations and uniparental disomies in cytogenetically normal acute myeloid leukemia using high-resolution single-nucleotide polymorphism analysis., Leukemia, 24, 438, 10.1038/leu.2009.263 Rucker, 2006, Disclosure of candidate genes in acute myeloid leukemia with complex karyotypes using microarray-based molecular characterization., J Clin Oncol, 24, 3887, 10.1200/JCO.2005.04.5450 Rucker, 2012, TP53 alterations in acute myeloid leukemia with complex karyotype correlate with specific copy number alterations, monosomal karyotype, and dismal outcome., Blood, 119, 2114, 10.1182/blood-2011-08-375758 Luck, 2010, KIT mutations confer a distinct gene expression signature in core binding factor leukaemia., Br J Haematol, 148, 925, 10.1111/j.1365-2141.2009.08035.x Ashburner, 2000, Gene ontology: tool for the unification of biology. The Gene Ontology Consortium., Nat Genet, 25, 25, 10.1038/75556 Falcon, 2007, Using GOstats to test gene lists for GO term association., Bioinformatics, 23, 257, 10.1093/bioinformatics/btl567 Abdel-Wahab, 2009, Genetic characterization of TET1, TET2, and TET3 alterations in myeloid malignancies., Blood, 114, 144, 10.1182/blood-2009-03-210039 Bamford, 2004, The COSMIC (Catalogue of Somatic Mutations in Cancer) database and website., Br J Cancer, 91, 355, 10.1038/sj.bjc.6601894 Kim, 2004, Dnmt1 deficiency leads to enhanced microsatellite instability in mouse embryonic stem cells., Nucleic Acids Res, 32, 5742, 10.1093/nar/gkh912 Morrison, 2003, Sister chromatid cohesion and genome stability in vertebrate cells., Biochem Soc Trans, 31, 263, 10.1042/bst0310263 Essafi, 2011, A wt1-controlled chromatin switching mechanism underpins tissue-specific wnt4 activation and repression., Dev Cell, 21, 559, 10.1016/j.devcel.2011.07.014 Shukla, 2011, CTCF-promoted RNA polymerase II pausing links DNA methylation to splicing., Nature, 479, 74, 10.1038/nature10442 Gozani, 1994, A novel set of spliceosome-associated proteins and the essential splicing factor PSF bind stably to pre-mRNA prior to catalytic step II of the splicing reaction., EMBO J, 13, 3356, 10.1002/j.1460-2075.1994.tb06638.x Mathur, 2001, PSF is a novel corepressor that mediates its effect through Sin3A and the DNA binding domain of nuclear hormone receptors., Mol Cell Biol, 21, 2298, 10.1128/MCB.21.7.2298-2311.2001 Panigrahi, 2012, A cohesin-RAD21 interactome., Biochem J, 442, 661, 10.1042/BJ20111745 Gaidzik, 2011, RUNX1 mutations in acute myeloid leukemia: results from a comprehensive genetic and clinical analysis from the AML study group., J Clin Oncol, 29, 1364, 10.1200/JCO.2010.30.7926 Dohner, 2003, Mutation analysis of the transcription factor PU. 1 in younger adults (16 to 60 years) with acute myeloid leukemia: a study of the AML Study Group Ulm (AMLSG ULM)., Blood, 102, 10.1182/blood-2003-08-2654 Tefferi, 2010, Novel mutations and their functional and clinical relevance in myeloproliferative neoplasms: JAK2, MPL, TET2, ASXL1, CBL, IDH and IKZF1., Leukemia, 24, 1128, 10.1038/leu.2010.69 Gui, 2011, Frequent mutations of chromatin remodeling genes in transitional cell carcinoma of the bladder., Nat Genet, 43, 875, 10.1038/ng.907 Parsons, 2011, The genetic landscape of the childhood cancer medulloblastoma., Science, 331, 435, 10.1126/science.1198056 Kagey, 2010, Mediator and cohesin connect gene expression and chromatin architecture., Nature, 467, 430, 10.1038/nature09380 Nitzsche, 2011, RAD21 cooperates with pluripotency transcription factors in the maintenance of embryonic stem cell identity., PLoS One, 6, e19470, 10.1371/journal.pone.0019470 Mullighan, 2011, CREBBP mutations in relapsed acute lymphoblastic leukaemia., Nature, 471, 235, 10.1038/nature09727 Wada, 2009, A wave of nascent transcription on activated human genes., Proc Natl Acad Sci U S A, 106, 18357, 10.1073/pnas.0902573106 Dorsett, 2011, Cohesin: genomic insights into controlling gene transcription and development., Curr Opin Genet Dev, 21, 199, 10.1016/j.gde.2011.01.018 Hadjur, 2009, Cohesins form chromosomal cis-interactions at the developmentally regulated IFNG locus., Nature, 460, 410, 10.1038/nature08079 Xu, 2012, Rad21-cohesin haploinsufficiency impedes DNA repair and enhances gastrointestinal radiosensitivity in mice., PLoS One, 5, e12112, 10.1371/journal.pone.0012112 Poleshko, 2010, Identification of a functional network of human epigenetic silencing factors., J Biol Chem, 285, 422, 10.1074/jbc.M109.064667 Brassesco, 2011, Secondary PSF/TFE3-associated renal cell carcinoma in a child treated for genitourinary rhabdomyosarcoma., Cancer Genet, 204, 108, 10.1016/j.cancergencyto.2010.10.006 Duhoux, 2011, The t(1;9)(p34;q34) fusing ABL1 with SFPQ, a pre-mRNA processing gene, is recurrent in acute lymphoblastic leukemias., Leuk Res, 35, e114, 10.1016/j.leukres.2011.02.011 Patton, 1993, Cloning and characterization of PSF, a novel pre-mRNA splicing factor., Genes Dev, 7, 393, 10.1101/gad.7.3.393