title: Mutations of NOTCH1 are an independent predictor of survival in chronic lymphocytic leukemia.
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.
authors.affiliation: Division of Hematology, Department of Clinical and Experimental Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy. rossidav@med.unipmn.it
authors.forename: Davide
authors.initials: D
authors.lastname: Rossi
authors.forename: Silvia
authors.initials: S
authors.lastname: Rasi
authors.forename: Giulia
authors.initials: G
authors.lastname: Fabbri
authors.forename: Valeria
authors.initials: V
authors.lastname: Spina
authors.forename: Marco
authors.initials: M
authors.lastname: Fangazio
authors.forename: Francesco
authors.initials: F
authors.lastname: Forconi
authors.forename: Roberto
authors.initials: R
authors.lastname: Marasca
authors.forename: Luca
authors.initials: L
authors.lastname: Laurenti
authors.forename: Alessio
authors.initials: A
authors.lastname: Bruscaggin
authors.forename: Michaela
authors.initials: M
authors.lastname: Cerri
authors.forename: Sara
authors.initials: S
authors.lastname: Monti
authors.forename: Stefania
authors.initials: S
authors.lastname: Cresta
authors.forename: Rosella
authors.initials: R
authors.lastname: Famà
authors.forename: Lorenzo
authors.initials: L
authors.lastname: De Paoli
authors.forename: Pietro
authors.initials: P
authors.lastname: Bulian
authors.forename: Valter
authors.initials: V
authors.lastname: Gattei
authors.forename: Anna
authors.initials: A
authors.lastname: Guarini
authors.forename: Silvia
authors.initials: S
authors.lastname: Deaglio
authors.forename: Daniela
authors.initials: D
authors.lastname: Capello
authors.forename: Raul
authors.initials: R
authors.lastname: Rabadan
authors.forename: Laura
authors.initials: L
authors.lastname: Pasqualucci
authors.forename: Riccardo
authors.initials: R
authors.lastname: Dalla-Favera
authors.forename: Robin
authors.initials: R
authors.lastname: Foà
authors.forename: Gianluca
authors.initials: G
authors.lastname: Gaidano
mesh_terms: D000368:Aged; D002471:Cell Transformation, Neoplastic; D002881:Chromosomes, Human, Pair 12 / Q000235:genetics; D018450:Disease Progression; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D007135:Immunoglobulin Variable Region / Q000235:genetics; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000401:mortality*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D011379:Prognosis; D011446:Prospective Studies; D000090063:Proto-Oncogene Mas; D051881:Receptor, Notch1 / Q000235:genetics*; D012307:Risk Factors; D015996:Survival Rate; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region; C000715470:MAS1 protein, human; C497761:NOTCH1 protein, human; D000090063:Proto-Oncogene Mas; D051881:Receptor, Notch1; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53
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