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

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 thre...

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Autores principales: Fontana, Maria Chiara, Marconi, Giovanni, Feenstra, Jelena D. Milosevic, Fonzi, Eugenio, Papayannidis, Cristina, Ghelli Luserna di Rorá, Andrea, Padella, Antonella, Solli, Vincenza, Franchini, Eugenia, Ottaviani, Emanuela, Ferrari, Anna, Baldazzi, Carmen, Testoni, Nicoletta, Iacobucci, Ilaria, Soverini, Simona, Haferlach, Torsten, Guadagnuolo, Viviana, Semerad, Lukas, Doubek, Michael, Steurer, Michael, Racil, Zdenek, Paolini, Stefania, Manfrini, Marco, Cavo, Michele, Simonetti, Giorgia, Kralovics, Robert, Martinelli, Giovanni
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6035145/
https://www.ncbi.nlm.nih.gov/pubmed/29472722
http://dx.doi.org/10.1038/s41375-018-0035-y
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author Fontana, Maria Chiara
Marconi, Giovanni
Feenstra, Jelena D. Milosevic
Fonzi, Eugenio
Papayannidis, Cristina
Ghelli Luserna di Rorá, Andrea
Padella, Antonella
Solli, Vincenza
Franchini, Eugenia
Ottaviani, Emanuela
Ferrari, Anna
Baldazzi, Carmen
Testoni, Nicoletta
Iacobucci, Ilaria
Soverini, Simona
Haferlach, Torsten
Guadagnuolo, Viviana
Semerad, Lukas
Doubek, Michael
Steurer, Michael
Racil, Zdenek
Paolini, Stefania
Manfrini, Marco
Cavo, Michele
Simonetti, Giorgia
Kralovics, Robert
Martinelli, Giovanni
author_facet Fontana, Maria Chiara
Marconi, Giovanni
Feenstra, Jelena D. Milosevic
Fonzi, Eugenio
Papayannidis, Cristina
Ghelli Luserna di Rorá, Andrea
Padella, Antonella
Solli, Vincenza
Franchini, Eugenia
Ottaviani, Emanuela
Ferrari, Anna
Baldazzi, Carmen
Testoni, Nicoletta
Iacobucci, Ilaria
Soverini, Simona
Haferlach, Torsten
Guadagnuolo, Viviana
Semerad, Lukas
Doubek, Michael
Steurer, Michael
Racil, Zdenek
Paolini, Stefania
Manfrini, Marco
Cavo, Michele
Simonetti, Giorgia
Kralovics, Robert
Martinelli, Giovanni
author_sort Fontana, Maria Chiara
collection PubMed
description 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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spelling pubmed-60351452018-07-09 Chromothripsis in acute myeloid leukemia: biological features and impact on survival Fontana, Maria Chiara Marconi, Giovanni Feenstra, Jelena D. Milosevic Fonzi, Eugenio Papayannidis, Cristina Ghelli Luserna di Rorá, Andrea Padella, Antonella Solli, Vincenza Franchini, Eugenia Ottaviani, Emanuela Ferrari, Anna Baldazzi, Carmen Testoni, Nicoletta Iacobucci, Ilaria Soverini, Simona Haferlach, Torsten Guadagnuolo, Viviana Semerad, Lukas Doubek, Michael Steurer, Michael Racil, Zdenek Paolini, Stefania Manfrini, Marco Cavo, Michele Simonetti, Giorgia Kralovics, Robert Martinelli, Giovanni Leukemia Article 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. Nature Publishing Group UK 2018-02-23 2018 /pmc/articles/PMC6035145/ /pubmed/29472722 http://dx.doi.org/10.1038/s41375-018-0035-y Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, and provide a link to the Creative Commons license. You do not have permission under this license to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.
spellingShingle Article
Fontana, Maria Chiara
Marconi, Giovanni
Feenstra, Jelena D. Milosevic
Fonzi, Eugenio
Papayannidis, Cristina
Ghelli Luserna di Rorá, Andrea
Padella, Antonella
Solli, Vincenza
Franchini, Eugenia
Ottaviani, Emanuela
Ferrari, Anna
Baldazzi, Carmen
Testoni, Nicoletta
Iacobucci, Ilaria
Soverini, Simona
Haferlach, Torsten
Guadagnuolo, Viviana
Semerad, Lukas
Doubek, Michael
Steurer, Michael
Racil, Zdenek
Paolini, Stefania
Manfrini, Marco
Cavo, Michele
Simonetti, Giorgia
Kralovics, Robert
Martinelli, Giovanni
Chromothripsis in acute myeloid leukemia: biological features and impact on survival
title Chromothripsis in acute myeloid leukemia: biological features and impact on survival
title_full Chromothripsis in acute myeloid leukemia: biological features and impact on survival
title_fullStr Chromothripsis in acute myeloid leukemia: biological features and impact on survival
title_full_unstemmed Chromothripsis in acute myeloid leukemia: biological features and impact on survival
title_short Chromothripsis in acute myeloid leukemia: biological features and impact on survival
title_sort chromothripsis in acute myeloid leukemia: biological features and impact on survival
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6035145/
https://www.ncbi.nlm.nih.gov/pubmed/29472722
http://dx.doi.org/10.1038/s41375-018-0035-y
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