High‐throughput sequencing for the identification of NOTCH1 mutations in early stage chronic lymphocytic leukaemia: biological and clinical implications. (2nd March 2014)

• Record Type: Journal Article
• Authors: Lionetti, Marta; Fabris, Sonia; Cutrona, Giovanna; Agnelli, Luca; Ciardullo, Carmela; Matis, Serena; Ciceri, Gabriella; Colombo, Monica; Maura, Francesco; Mosca, Laura; Gentile, Massimo; Recchia, Anna G.; Ilariucci, Fiorella; Musolino, Caterina; Molica, Stefano; Di Raimondo, Francesco; Cortelezzi, Agostino; Rossi, Davide; Gaidano, Gianluca; Morabito, Fortunato; Ferrarini, Manlio; Neri, Antonino
• Is Part Of: British journal of haematology. Volume 165:Number 5(2014:Jun.)
• Page Start: 629
• Page End: 639
• Publication Date: 2014-03-02
• Subjects: Hematology -- Periodicals; Blood -- Diseases -- Periodicals; 616.15
• DOI: 10.1111/bjh.12800
• Languages: English
• ISSNs: 0007-1048

Abstract

<abstract abstract-type="main" id="bjh12800-abs-0001"> <title>Summary</title> <p> <italic>NOTCH1</italic> mutations have recently emerged as new genetic lesions significantly correlated with survival in chronic lymphocytic leukaemia (CLL). We performed deep next generation sequencing of the <italic>NOTCH1</italic> mutation hotspot in 384 cases at diagnosis, including 100 monoclonal B cell lymphocytosis (MBL) and 284 Binet stage A CLL cases, enrolled in the Gruppo Italiano Studio Linfomi O‐CLL1 multicentre trial. The <italic>NOTCH1</italic> c.7541_7542delCT dinucleotide deletion was detected and confirmed by an extremely sensitive polymerase chain reaction‐based approach in 11% of MBL and 13·4% of CLL patients. Remarkably, the <italic>NOTCH1</italic> mutation was often observed at low clonal level, mainly in MBL patients. Sequential analyses in a fraction of cases showed that the <italic>NOTCH1</italic> mutation generally does not occur during the disease course and that the mutational load in positive cases tends to be stable over time. <italic>NOTCH1</italic>‐mutated cases, even at low clonal level, displayed a significant reduction in median progression‐free survival, although <italic>NOTCH1</italic> mutation lost its prognostic impact in a multivariate analysis including 11q and/or 17p deletion, <italic>IGHV</italic> mutational status, and MBL or CLL status. Our data highlight the importance of using highly sensitive methods to measure <italic>NOTCH1</italic> mutations, in order to improve prognostic stratification and obtain useful information for potential therapeutic approaches.</p> </abstract>