title: Marker chromosomes can arise from chromothripsis and predict adverse prognosis in acute myeloid leukemia.
abstract: Metaphase karyotyping is an established diagnostic standard in acute myeloid leukemia (AML) for risk stratification. One of the cytogenetic findings in AML is structurally highly abnormal marker chromosomes. In this study, we have assessed frequency, cytogenetic characteristics, prognostic impact, and underlying biological origin of marker chromosomes. Given their inherent gross structural chromosomal damage, we speculated that they may arise from chromothripsis, a recently described phenomenon of chromosome fragmentation in a single catastrophic event. In 2 large consecutive prospective, randomized, multicenter, intensive chemotherapy trials (AML96, AML2003) from the Study Alliance Leukemia, marker chromosomes were detectable in 165/1026 (16.1%) of aberrant non-core-binding-factor (CBF) karyotype patients. Adverse-risk karyotypes displayed a higher frequency of marker chromosomes (26.5% in adverse-risk, 40.3% in complex aberrant, and 41.2% in abnormality(17p) karyotypes,P< .0001 each). Marker chromosomes were associated with a poorer prognosis compared with other non-CBF aberrant karyotypes and led to lower remission rates (complete remission + complete remission with incomplete recovery), inferior event-free survival as well as overall survival in both trials. In multivariate analysis, marker chromosomes independently predicted poor prognosis in the AML96 trial ≤60 years. As detected by array comparative genomic hybridization, about one-third of marker chromosomes (18/49) had arisen from chromothripsis, whereas this phenomenon was virtually undetectable in a control group of marker chromosome-negative complex aberrant karyotypes (1/34). The chromothripsis-positive cases were characterized by a particularly high degree of karyotype complexity,TP53mutations, and dismal prognosis. In conclusion, marker chromosomes are indicative of chromothripsis and associated with poor prognosis per se and not merely by association with other adverse cytogenetic features.
authors.affiliation: Clinical Cooperation Unit Molecular Hematology/Oncology, German Cancer Research Center.|Department of Internal Medicine V, and.
authors.forename: Tilmann
authors.initials: T
authors.lastname: Bochtler
authors.affiliation: Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Granzow
authors.affiliation: Department of Internal Medicine I, University Hospital Carl Gustav Carus, Dresden, Germany.
authors.forename: Friedrich
authors.initials: F
authors.lastname: Stölzel
authors.affiliation: Division of Biostatistics, German Cancer Research Center, Heidelberg, Germany; and.
authors.forename: Christina
authors.initials: C
authors.lastname: Kunz
authors.affiliation: Department of Internal Medicine I, University Hospital Carl Gustav Carus, Dresden, Germany.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Mohr
authors.affiliation: Clinical Cooperation Unit Molecular Hematology/Oncology, German Cancer Research Center.|Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany.|Department of Pediatric Oncology, Hematology and Immunology, and.
authors.forename: Mutlu
authors.initials: M
authors.lastname: Kartal-Kaess
authors.affiliation: Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Hinderhofer
authors.affiliation: Clinical Cooperation Unit Molecular Hematology/Oncology, German Cancer Research Center.|Department of Internal Medicine V, and.
authors.forename: Christoph E
authors.initials: CE
authors.lastname: Heilig
authors.affiliation: Department of Internal Medicine I, University Hospital Carl Gustav Carus, Dresden, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Kramer
authors.affiliation: Department of Internal Medicine I, University Hospital Carl Gustav Carus, Dresden, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Thiede
authors.affiliation: Institute of Pathology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Endris
authors.affiliation: Institute of Pathology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Kirchner
authors.affiliation: Institute of Pathology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Albrecht
authors.initials: A
authors.lastname: Stenzinger
authors.affiliation: Division of Biostatistics, German Cancer Research Center, Heidelberg, Germany; and.
authors.forename: Axel
authors.initials: A
authors.lastname: Benner
authors.affiliation: Department of Internal Medicine I, University Hospital Carl Gustav Carus, Dresden, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Bornhäuser
authors.affiliation: Department of Internal Medicine I, University Hospital Carl Gustav Carus, Dresden, Germany.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Ehninger
authors.affiliation: Department of Internal Medicine V, and.
authors.forename: Anthony D
authors.initials: AD
authors.lastname: Ho
authors.affiliation: Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Jauch
authors.affiliation: Clinical Cooperation Unit Molecular Hematology/Oncology, German Cancer Research Center.|Department of Internal Medicine V, and.
authors.forename: Alwin
authors.initials: A
authors.lastname: Krämer
mesh_terms: D059786:Abnormal Karyotype; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics*; D000072837:Chromothripsis; D055028:Comparative Genomic Hybridization; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D053208:Kaplan-Meier Estimate; D007621:Karyotyping; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D016016:Proportional Hazards Models; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor