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Leukemia. 2018 Jul;32(7):1609-1620. doi: 10.1038/s41375-018-0035-y. Epub 2018 Feb 23.

Chromothripsis in acute myeloid leukemia: biological features and impact on survival.

Author information

1
Institute of Hematology "L. and A. Seràgnoli", University of Bologna, Bologna, Italy. mariachiara.fontana4@unibo.it.
2
Institute of Hematology "L. and A. Seràgnoli", University of Bologna, Bologna, Italy. giovanni.marconi@studio.unibo.it.
3
CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Wien, Austria.
4
Institute of Hematology "L. and A. Seràgnoli", University of Bologna, Bologna, Italy.
5
Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA.
6
MLL Munich Leukemia Laboratory, Munich, Germany.
7
Department of Internal Medicine - Hematology and Oncology, Masaryk University and Hospital, Brno, Czech Republic.
8
Division of Hematology and Oncology, Medical University of Innsbruck, Innsbruck, Austria.
9
Institute of Hematology "L. and A. Seràgnoli", University of Bologna, Bologna, Italy. giovanni.martinelli2@unibo.it.

Abstract

Chromothripsis is a one-step genome-shattering catastrophe resulting from disruption of one or few chromosomes in multiple fragments and consequent random rejoining and repair. This study defines incidence of chromothripsis in 395 newly diagnosed adult acute myeloid leukemia (AML) patients from three institutions, its impact on survival and its genomic background. SNP 6.0 or CytoscanHD Array (Affymetrix®) were performed on all samples. We detected chromothripsis with a custom algorithm in 26/395 patients. Patients harboring chromothripsis had higher age (p = 0.002), ELN high risk (HR) (p < 0.001), lower white blood cell (WBC) count (p = 0.040), TP53 loss, and/or mutations (p < 0.001) while FLT3 (p = 0.025), and NPM1 (p = 0.032) mutations were mutually exclusive with chromothripsis. Chromothripsis-positive patients showed a worse overall survival (OS) (p < 0.001) compared with HR patients (p = 0.011) and a poor prognosis in a COX-HR optimal regression model. Chromothripsis presented the hallmarks of chromosome instability [i.e., TP53 alteration, 5q deletion, higher mean of copy number alteration (CNA), complex karyotype, alterations in DNA repair, and cell cycle] and focal deletions on chromosomes 4, 7, 12, 16, and 17. CBA. FISH showed that chromothripsis is associated with marker, derivative, and ring chromosomes. In conclusion, chromothripsis frequently occurs in AML (6.6%) and influences patient prognosis and disease biology.

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