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

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

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)521-529
Number of pages9
JournalBlood
Volume119
Issue number2
DOIs
Publication statusPublished - Jan 12 2012

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

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    Rossi, D., Rasi, S., Fabbri, G., Spina, V., Fangazio, M., Forconi, F., Marasca, R., Laurenti, L., Bruscaggin, A., Cerri, M., Monti, S., Cresta, S., Famà, R., De Paoli, L., Bulian, P., Gattei, V., Guarini, A., Deaglio, S., Capello, D., ... Gaidano, G. (2012). Mutations of NOTCH1 are an independent predictor of survival in chronic lymphocytic leukemia. Blood, 119(2), 521-529. https://doi.org/10.1182/blood-2011-09-379966