title: Isolated trisomy 13 defines a homogeneous AML subgroup with high frequency of mutations in spliceosome genes and poor prognosis.
abstract: In acute myeloid leukemia (AML), isolated trisomy 13 (AML+13) is a rare chromosomal abnormality whose prognostic relevance is poorly characterized. We analyzed the clinical course of 34 AML+13 patients enrolled in the German AMLCG-1999 and SAL trials and performed exome sequencing, targeted candidate gene sequencing and gene expression profiling. Relapse-free (RFS) and overall survival (OS) of AML+13 patients were inferior compared to other ELN Intermediate-II patients (n=855) (median RFS, 7.8 vs 14.1 months, P = .006; median OS 9.3 vs. 14.8 months, P = .004). Besides the known high frequency of RUNX1 mutations (75%), we identified mutations in spliceosome components in 88%, including SRSF2 codon 95 mutations in 81%. Recurring mutations were detected in ASXL1 (44%) and BCOR (25%). Two patients carried mutations in CEBPZ, suggesting that CEBPZ is a novel recurrently mutated gene in AML. Gene expression analysis revealed a homogeneous expression profile including upregulation of FOXO1 and FLT3 and downregulation of SPRY2. This is the most comprehensive clinical and biological characterization of AML+13 to date, and reveals a striking clustering of lesions in a few genes, defining AML+13 as a genetically homogeneous subgroup with alterations in a few critical cellular pathways. Clinicaltrials.gov identifiers: AMLCG-1999: NCT00266136; AML96: NCT00180115; AML2003: NCT00180102; and AML60+: NCT00893373.
authors.affiliation: Department of Internal Medicine 3, University Hospital Grosshadern, Ludwig-Maximilians-Universität, Munich, Germany; Clinical Cooperative Group Leukemia, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany;
authors.forename: Tobias
authors.initials: T
authors.lastname: Herold
authors.affiliation: Department of Internal Medicine 3, University Hospital Grosshadern, Ludwig-Maximilians-Universität, Munich, Germany; Clinical Cooperative Group Leukemia, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany;
authors.forename: Klaus H
authors.initials: KH
authors.lastname: Metzeler
authors.affiliation: Department of Internal Medicine 3, University Hospital Grosshadern, Ludwig-Maximilians-Universität, Munich, Germany; Clinical Cooperative Group Leukemia, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany;
authors.forename: Sebastian
authors.initials: S
authors.lastname: Vosberg
authors.affiliation: Department of Internal Medicine 3, University Hospital Grosshadern, Ludwig-Maximilians-Universität, Munich, Germany; Clinical Cooperative Group Leukemia, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany;
authors.forename: Luise
authors.initials: L
authors.lastname: Hartmann
authors.affiliation: German Cancer Consortium (DKTK), Heidelberg, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany; Medizinische Klinik und Poliklinik I, Universitätsklinikum Dresden, Dresden, Germany;
authors.forename: Christoph
authors.initials: C
authors.lastname: Röllig
authors.affiliation: Medizinische Klinik und Poliklinik I, Universitätsklinikum Dresden, Dresden, Germany;
authors.forename: Friedrich
authors.initials: F
authors.lastname: Stölzel
authors.affiliation: Department of Internal Medicine 3, University Hospital Grosshadern, Ludwig-Maximilians-Universität, Munich, Germany;
authors.forename: Stephanie
authors.initials: S
authors.lastname: Schneider
authors.affiliation: Department of Internal Medicine 3, University Hospital Grosshadern, Ludwig-Maximilians-Universität, Munich, Germany; Clinical Cooperative Group Leukemia, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany;
authors.forename: Max
authors.initials: M
authors.lastname: Hubmann
authors.affiliation: Department of Internal Medicine 3, University Hospital Grosshadern, Ludwig-Maximilians-Universität, Munich, Germany;
authors.forename: Evelyn
authors.initials: E
authors.lastname: Zellmeier
authors.affiliation: Department of Internal Medicine 3, University Hospital Grosshadern, Ludwig-Maximilians-Universität, Munich, Germany;
authors.forename: Bianka
authors.initials: B
authors.lastname: Ksienzyk
authors.affiliation: Institute for Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany;
authors.forename: Vindi
authors.initials: V
authors.lastname: Jurinovic
authors.affiliation: Department of Internal Medicine 3, University Hospital Grosshadern, Ludwig-Maximilians-Universität, Munich, Germany;
authors.forename: Zlatana
authors.initials: Z
authors.lastname: Pasalic
authors.affiliation: Center for Human Genetics, Philipps University, Marburg, Germany;
authors.forename: Purvi M
authors.initials: PM
authors.lastname: Kakadia
authors.affiliation: Department of Internal Medicine 3, University Hospital Grosshadern, Ludwig-Maximilians-Universität, Munich, Germany;
authors.forename: Annika
authors.initials: A
authors.lastname: Dufour
authors.affiliation: Laboratory for Functional Genome Analysis (LAFUGA), Gene Center, Ludwig-Maximilians-Universität, Munich, Germany;
authors.forename: Alexander
authors.initials: A
authors.lastname: Graf
authors.affiliation: Laboratory for Functional Genome Analysis (LAFUGA), Gene Center, Ludwig-Maximilians-Universität, Munich, Germany;
authors.forename: Stefan
authors.initials: S
authors.lastname: Krebs
authors.affiliation: Laboratory for Functional Genome Analysis (LAFUGA), Gene Center, Ludwig-Maximilians-Universität, Munich, Germany;
authors.forename: Helmut
authors.initials: H
authors.lastname: Blum
authors.affiliation: Institute of Biostatistics and Clinical Research, and.
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: Sauerland
authors.affiliation: Department of Medicine A - Hematology, Oncology and Pneumology, University of Münster, Münster, Germany;
authors.forename: Thomas
authors.initials: T
authors.lastname: Büchner
authors.affiliation: Department of Medicine A - Hematology, Oncology and Pneumology, University of Münster, Münster, Germany;
authors.forename: Wolfgang E
authors.initials: WE
authors.lastname: Berdel
authors.affiliation: German Society of Hematology and Oncology, Berlin, Germany; and.
authors.forename: Bernhard J
authors.initials: BJ
authors.lastname: Woermann
authors.affiliation: German Cancer Consortium (DKTK), Heidelberg, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany; Medizinische Klinik und Poliklinik I, Universitätsklinikum Dresden, Dresden, Germany;
authors.forename: Martin
authors.initials: M
authors.lastname: Bornhäuser
authors.affiliation: German Cancer Consortium (DKTK), Heidelberg, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany; Medizinische Klinik und Poliklinik I, Universitätsklinikum Dresden, Dresden, Germany;
authors.forename: Gerhard
authors.initials: G
authors.lastname: Ehninger
authors.affiliation: German Cancer Consortium (DKTK), Heidelberg, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany; Institute for Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany;
authors.forename: Ulrich
authors.initials: U
authors.lastname: Mansmann
authors.affiliation: Department of Internal Medicine 3, University Hospital Grosshadern, Ludwig-Maximilians-Universität, Munich, Germany; Clinical Cooperative Group Leukemia, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany;
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Hiddemann
authors.affiliation: Department of Molecular Medicine and Pathology, The University of Auckland, Auckland, New Zealand.
authors.forename: Stefan K
authors.initials: SK
authors.lastname: Bohlander
authors.affiliation: Department of Internal Medicine 3, University Hospital Grosshadern, Ludwig-Maximilians-Universität, Munich, Germany; Clinical Cooperative Group Leukemia, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany;
authors.forename: Karsten
authors.initials: K
authors.lastname: Spiekermann
authors.affiliation: Department of Internal Medicine 3, University Hospital Grosshadern, Ludwig-Maximilians-Universität, Munich, Germany; Clinical Cooperative Group Leukemia, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany;
authors.forename: Philipp A
authors.initials: PA
authors.lastname: Greif
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002882:Chromosomes, Human, Pair 13 / Q000235:genetics / Q000378:metabolism; D018572:Disease-Free Survival; D005260:Female; D015973:Gene Expression Regulation, Leukemic / Q000235:genetics*; D005858:Germany / Q000453:epidemiology; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D015996:Survival Rate; D014314:Trisomy / Q000235:genetics / Q000473:pathology; D015854:Up-Regulation / Q000235:genetics*
chemical_list: D009363:Neoplasm Proteins