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Mutations of NOTCH1 are an independent predictor of survival in chronic lymphocytic leukemia

Mutations of NOTCH1 are an independent predictor of survival in chronic lymphocytic leukemia
Mutations of NOTCH1 are an independent predictor of survival in chronic lymphocytic leukemia
Analysis of the chronic lymphocytic leukemia (CLL) coding genome has recently disclosed that the NOTCH1 proto-oncogene is recurrently mutated at CLL presentation. Here, we assessed the prognostic role of NOTCH1 mutations in CLL. Two series of newly diagnosed CLL were used as training (n = 309) and validation (n = 230) cohorts. NOTCH1 mutations occurred in 11.0% and 11.3% CLL of the training and validation series, respectively. In the training series, NOTCH1 mutations led to a 3.77-fold increase in the hazard of death and to shorter overall survival (OS; P<.001). Multivariate analysis selected NOTCH1 mutations as an independent predictor of OS after controlling for confounding clinical and biologic variables. The independent prognostic value of NOTCH1 mutations was externally confirmed in the validation series. The poor prognosis conferred by NOTCH1 mutations was attributable, at least in part, to shorter treatment-free survival and higher risk of Richter transformation. Although NOTCH1 mutated patients were devoid of TP53 disruption in more than 90% cases in both training and validation series, the OS predicted by NOTCH1 mutations was similar to that of TP53 mutated/deleted CLL. NOTCH1 mutations are an independent predictor of CLL OS, tend to be mutually exclusive with TP53 abnormalities, and identify cases with a dismal prognosis.
0006-4971
521-529
Rossi, Davide
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Rasi, Silvia
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Fabbri, Giulia
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Spina, Valeria
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Fangazio, Marco
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Forconi, Francesco
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Marasca, Roberto
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Laurenti, Luca
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Bruscaggin, Alessio
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Cerri, Michaela
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Monti, Sara
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Cresta, Stefania
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Famà, Rosella
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De Paoli, Lorenzo
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Bulian, Pietro
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Gattei, Valter
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Guarini, Anna
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Deaglio, Silvia
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Capello, Daniela
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Rabadan, Raul
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Pasqualucci, Laura
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Dalla-Favera, Riccardo
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Foà, Robin
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Gaidano, Gianluca
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Rossi, Davide
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Rasi, Silvia
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Fabbri, Giulia
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Spina, Valeria
bb72602d-3d56-424f-b169-47377aef1d10
Fangazio, Marco
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Forconi, Francesco
ce9ed873-58cf-4876-bf3a-9ba1d163edc8
Marasca, Roberto
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Laurenti, Luca
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Bruscaggin, Alessio
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Cerri, Michaela
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Monti, Sara
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Cresta, Stefania
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Famà, Rosella
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De Paoli, Lorenzo
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Bulian, Pietro
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Gattei, Valter
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Guarini, Anna
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Deaglio, Silvia
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Capello, Daniela
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Rabadan, Raul
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Pasqualucci, Laura
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Dalla-Favera, Riccardo
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Foà, Robin
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Gaidano, Gianluca
1a6a7107-107b-4891-82e0-5fedadd2f65a

Rossi, Davide, Rasi, Silvia, Fabbri, Giulia, Spina, Valeria, Fangazio, Marco, Forconi, Francesco, Marasca, Roberto, Laurenti, Luca, Bruscaggin, Alessio, Cerri, Michaela, Monti, Sara, Cresta, Stefania, Famà, Rosella, De Paoli, Lorenzo, Bulian, Pietro, Gattei, Valter, Guarini, Anna, Deaglio, Silvia, Capello, Daniela, Rabadan, Raul, Pasqualucci, Laura, Dalla-Favera, Riccardo, Foà, Robin and Gaidano, Gianluca (2012) Mutations of NOTCH1 are an independent predictor of survival in chronic lymphocytic leukemia. Blood, 119 (2), 521-529. (doi:10.1182/blood-2011-09-379966). (PMID:22077063)

Record type: Article

Abstract

Analysis of the chronic lymphocytic leukemia (CLL) coding genome has recently disclosed that the NOTCH1 proto-oncogene is recurrently mutated at CLL presentation. Here, we assessed the prognostic role of NOTCH1 mutations in CLL. Two series of newly diagnosed CLL were used as training (n = 309) and validation (n = 230) cohorts. NOTCH1 mutations occurred in 11.0% and 11.3% CLL of the training and validation series, respectively. In the training series, NOTCH1 mutations led to a 3.77-fold increase in the hazard of death and to shorter overall survival (OS; P<.001). Multivariate analysis selected NOTCH1 mutations as an independent predictor of OS after controlling for confounding clinical and biologic variables. The independent prognostic value of NOTCH1 mutations was externally confirmed in the validation series. The poor prognosis conferred by NOTCH1 mutations was attributable, at least in part, to shorter treatment-free survival and higher risk of Richter transformation. Although NOTCH1 mutated patients were devoid of TP53 disruption in more than 90% cases in both training and validation series, the OS predicted by NOTCH1 mutations was similar to that of TP53 mutated/deleted CLL. NOTCH1 mutations are an independent predictor of CLL OS, tend to be mutually exclusive with TP53 abnormalities, and identify cases with a dismal prognosis.

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e-pub ahead of print date: 10 November 2011
Published date: 12 January 2012
Organisations: Cancer Sciences

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Local EPrints ID: 358115
URI: https://eprints.soton.ac.uk/id/eprint/358115
ISSN: 0006-4971
PURE UUID: eea4f722-b6ac-4850-b081-99cead343a4b

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Date deposited: 04 Oct 2013 11:01
Last modified: 16 Jul 2019 21:21

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Contributors

Author: Davide Rossi
Author: Silvia Rasi
Author: Giulia Fabbri
Author: Valeria Spina
Author: Marco Fangazio
Author: Roberto Marasca
Author: Luca Laurenti
Author: Alessio Bruscaggin
Author: Michaela Cerri
Author: Sara Monti
Author: Stefania Cresta
Author: Rosella Famà
Author: Lorenzo De Paoli
Author: Pietro Bulian
Author: Valter Gattei
Author: Anna Guarini
Author: Silvia Deaglio
Author: Daniela Capello
Author: Raul Rabadan
Author: Laura Pasqualucci
Author: Riccardo Dalla-Favera
Author: Robin Foà
Author: Gianluca Gaidano

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