title: Close correlation of copy number aberrations detected by next-generation sequencing with results from routine cytogenetics in acute myeloid leukemia.
abstract: High throughput sequencing approaches, including the analysis of exomes or gene panels, are widely used and established to detect tumor-specific sequence variants such as point mutations or small insertions/deletions. Beyond single nucleotide resolution, sequencing data also contain information on changes in sequence coverage between samples and thus allow the detection of somatic copy number alterations (CNAs) representing gain or loss of genomic material in tumor cells arising from aneuploidy, amplifications, or deletions. To test the feasibility of CNA detection in sequencing data we analyzed the exomes of 25 paired leukemia/remission samples from acute myeloid leukemia (AML) patients with well-defined chromosomal aberrations, detected by conventional chromosomal analysis and/or molecular cytogenetics assays. Thereby, we were able to confirm chromosomal aberrations including trisomies, monosomies, and partial chromosomal deletions in 20 out of 25 samples. Comparison of CNA detection using exome, custom gene panel, and SNP array analysis showed equivalent results in five patients with variable clone size. Gene panel analysis of AML samples without matched germline control samples resulted in confirmation of cytogenetic findings in 18 out of 22 cases. In all cases with discordant findings, small clone size (<33%) was limiting for CNA detection. We detected CNAs consistent with cytogenetics in 83% of AML samples including highly correlated clone size estimation (R = 0.85), while six out of 65 cytogenetically normal AML samples exhibited CNAs apparently missed by routine cytogenetics. Overall, our results show that high throughput targeted sequencing data can be reliably used to detect copy number changes in the dominant AML clone. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Experimental Leukemia and Lymphoma Research (ELLF), Department of Internal Medicine III, University Hospital of the Ludwig-Maximilians-Universität (LMU) München, Munich, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany.|Clinical Cooperative Group Leukemia, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Vosberg
authors.affiliation: German Cancer Research Center (DKFZ), Heidelberg, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany.|Laboratory for Leukemia Diagnostics, Department of Internal Medicine III, University Hospital of the Ludwig-Maximilians-Universität (LMU) München, Munich, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Herold
authors.affiliation: Experimental Leukemia and Lymphoma Research (ELLF), Department of Internal Medicine III, University Hospital of the Ludwig-Maximilians-Universität (LMU) München, Munich, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany.|Clinical Cooperative Group Leukemia, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany.
authors.forename: Luise
authors.initials: L
authors.lastname: Hartmann
authors.affiliation: German Cancer Research Center (DKFZ), Heidelberg, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany.|Department of Hematology and Oncology, Charité University Hospital, Berlin, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Neumann
authors.affiliation: German Cancer Research Center (DKFZ), Heidelberg, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany.|Laboratory for Leukemia Diagnostics, Department of Internal Medicine III, University Hospital of the Ludwig-Maximilians-Universität (LMU) München, Munich, Germany.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Opatz
authors.affiliation: German Cancer Research Center (DKFZ), Heidelberg, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany.|Laboratory for Leukemia Diagnostics, Department of Internal Medicine III, University Hospital of the Ludwig-Maximilians-Universität (LMU) München, Munich, Germany.
authors.forename: Klaus H
authors.initials: KH
authors.lastname: Metzeler
authors.affiliation: Laboratory for Leukemia Diagnostics, Department of Internal Medicine III, University Hospital of the Ludwig-Maximilians-Universität (LMU) München, Munich, Germany.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Schneider
authors.affiliation: Laboratory for Functional Genome Analysis (LAFUGA), Gene Center of the Ludwig-Maximilians-Universität (LMU) München, Munich, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Graf
authors.affiliation: Laboratory for Functional Genome Analysis (LAFUGA), Gene Center of the Ludwig-Maximilians-Universität (LMU) München, Munich, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Krebs
authors.affiliation: Laboratory for Functional Genome Analysis (LAFUGA), Gene Center of the Ludwig-Maximilians-Universität (LMU) München, Munich, Germany.
authors.forename: Helmut
authors.initials: H
authors.lastname: Blum
authors.affiliation: Department of Hematology and Oncology, Charité University Hospital, Berlin, Germany.
authors.forename: Claudia D
authors.initials: CD
authors.lastname: Baldus
authors.affiliation: Experimental Leukemia and Lymphoma Research (ELLF), Department of Internal Medicine III, University Hospital of the Ludwig-Maximilians-Universität (LMU) München, Munich, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany.|Clinical Cooperative Group Leukemia, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Hiddemann
authors.affiliation: Experimental Leukemia and Lymphoma Research (ELLF), Department of Internal Medicine III, University Hospital of the Ludwig-Maximilians-Universität (LMU) München, Munich, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany.|Clinical Cooperative Group Leukemia, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany.
authors.forename: Karsten
authors.initials: K
authors.lastname: Spiekermann
authors.affiliation: Molecular Medicine and Pathology, the University of Auckland, New Zealand.
authors.forename: Stefan K
authors.initials: SK
authors.lastname: Bohlander
authors.affiliation: German Cancer Research Center (DKFZ), Heidelberg, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany.|Institute for Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-Universität (LMU) München, Munich, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Mansmann
authors.affiliation: Experimental Leukemia and Lymphoma Research (ELLF), Department of Internal Medicine III, University Hospital of the Ludwig-Maximilians-Universität (LMU) München, Munich, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany.|Clinical Cooperative Group Leukemia, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany.
authors.forename: Philipp A
authors.initials: PA
authors.lastname: Greif
mesh_terms: D016022:Case-Control Studies; D002869:Chromosome Aberrations; D055028:Comparative Genomic Hybridization; D020732:Cytogenetic Analysis; D056915:DNA Copy Number Variations / Q000235:genetics*; D005500:Follow-Up Studies; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000473:pathology; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011379:Prognosis