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Multicenter Study
. 2012 Mar;97(3):437-41.
doi: 10.3324/haematol.2011.060129. Epub 2011 Dec 29.

NOTCH1 mutations in +12 chronic lymphocytic leukemia (CLL) confer an unfavorable prognosis, induce a distinctive transcriptional profiling and refine the intermediate prognosis of +12 CLL

Ilaria Del Giudice  1 , Davide Rossi, Sabina Chiaretti, Marilisa Marinelli, Simona Tavolaro, Sara Gabrielli, Luca Laurenti, Roberto Marasca, Silvia Rasi, Marco Fangazio, Anna Guarini, Gianluca Gaidano, Robin Foà
Affiliations
Multicenter Study

NOTCH1 mutations in +12 chronic lymphocytic leukemia (CLL) confer an unfavorable prognosis, induce a distinctive transcriptional profiling and refine the intermediate prognosis of +12 CLL

Ilaria Del Giudice et al. Haematologica. 2012 Mar.

Abstract

Trisomy 12, the third most frequent chromosomal aberration in chronic lymphocytic leukemia (CLL), confers an intermediate prognosis. In our cohort of 104 untreated patients carrying +12, NOTCH1 mutations occurred in 24% of cases and were associated to unmutated IGHV genes (P=0.003) and +12 as a sole cytogenetic abnormality (P=0.008). NOTCH1 mutations in +12 CLL associated with an approximately 2.4 fold increase in the risk of death, a significant shortening of survival (P<0.01) and proved to be an independent predictor of survival in multivariate analysis. Analogous to +12 CLL with TP53 disruption or del(11q), NOTCH1 mutations in +12 CLL conferred a significantly worse survival compared to that of +12 CLL with del(13q) or +12 only. The overrepresentation of cell cycle/proliferation related genes of +12 CLL with NOTCH1 mutations suggests the biological contribution of NOTCH1 mutations to determine a poor outcome. NOTCH1 mutations refine the intermediate prognosis of +12 CLL.

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Figures

Figure 1
Figure 1
(A) Distribution of NOTCH1 mutations among genetic subgroups of +12 CLL. (B) Overall survival according to NOTCH1 mutation status in +12 CLL. (C) Hierarchical stratification of overall survival according to genetic lesions in +12 CLL. (D) Comparison between NOTCH1 mutated and NOTCH1 wt CLL samples. Relative levels of gene expression are depicted with a color scale: red represents the highest level of expression and blue represents the lowest level. The table reports the functional annotation analysis, performed using the DAVID database, of differentially expressed genes between NOTCH1 mutated and NOTCH1 wt CLL. The biological processes reported are ordered according to their P value.
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