TY - JOUR
T1 - The notch pathway is recurrently mutated in diffuse large B-Cell lymphoma associated with hepatitis c virus infection
AU - Arcaini, Luca
AU - Rossi, Davide
AU - Lucioni, Marco
AU - Nicola, Marta
AU - Bruscaggin, Alessio
AU - Fiaccadori, Valeria
AU - Riboni, Roberta
AU - Ramponi, Antonio
AU - Ferretti, Virginia V.
AU - Cresta, Stefania
AU - Casaluci, Gloria Margiotta
AU - Bonfichi, Maurizio
AU - Gotti, Manuel
AU - Merli, Michele
AU - Maffi, Aldo
AU - Arra, Mariarosa
AU - Varettoni, Marzia
AU - Rattotti, Sara
AU - Morello, Lucia
AU - Guerrera, Maria Luisa
AU - Sciarra, Roberta
AU - Gaidano, Gianluca
AU - Cazzola, Mario
AU - Paulli, Marco
N1 - Publisher Copyright:
©2015 Ferrata Storti Foundation.
PY - 2015
Y1 - 2015
N2 - Hepatitis C virus has been found to be associated with B-cell non-Hodgkin lymphomas, mostly marginal zone lym-phomas and diffuse large B-cell lymphoma. Deregulation of signaling pathways involved in normal marginal zone development (NOTCH pathway, NF-κB, and BCR signaling) has been demonstrated in splenic marginal zone lym-phoma. We studied mutations of NOTCH pathway signaling in 46 patients with hepatitis C virus-positive diffuse large B-cell lymphoma and in 64 patients with diffuse large B-cell lymphoma unrelated to HCV. NOTCH2 mutations were detected in 9 of 46 (20%) hepatitis C virus-positive patients, and NOTCH1 mutations in 2 of 46 (4%). By contrast, only one of 64 HCV-negative patients had a NOTCH1 or NOTCH2 mutation. The frequency of the NOTCH pathway lesions was significantly higher in hepatitis C virus-positive patients (P=0.002). The 5-year overall survival was 27% (95%CI: 5%-56%) for hepatitis C virus-positive diffuse large B-cell lymphoma patients carrying a NOTCH pathway mutation versus 62% (95%CI: 42%-77%) for those without these genetic lesions. By uni-variate analysis, age over 60 years, NOTCH2 mutation, and any mutation of the NOTCH pathway (NOTCH2, NOTCH1, SPEN) were associated with shorter overall survival. Mutation of the NOTCH pathway retained an independent significance (P=0.029). In conclusion, a subset of patients with hepatitis C virus-positive diffuse large B-cell lymphoma displays a molecular signature of splenic marginal zone and has a worse clinical outcome.
AB - Hepatitis C virus has been found to be associated with B-cell non-Hodgkin lymphomas, mostly marginal zone lym-phomas and diffuse large B-cell lymphoma. Deregulation of signaling pathways involved in normal marginal zone development (NOTCH pathway, NF-κB, and BCR signaling) has been demonstrated in splenic marginal zone lym-phoma. We studied mutations of NOTCH pathway signaling in 46 patients with hepatitis C virus-positive diffuse large B-cell lymphoma and in 64 patients with diffuse large B-cell lymphoma unrelated to HCV. NOTCH2 mutations were detected in 9 of 46 (20%) hepatitis C virus-positive patients, and NOTCH1 mutations in 2 of 46 (4%). By contrast, only one of 64 HCV-negative patients had a NOTCH1 or NOTCH2 mutation. The frequency of the NOTCH pathway lesions was significantly higher in hepatitis C virus-positive patients (P=0.002). The 5-year overall survival was 27% (95%CI: 5%-56%) for hepatitis C virus-positive diffuse large B-cell lymphoma patients carrying a NOTCH pathway mutation versus 62% (95%CI: 42%-77%) for those without these genetic lesions. By uni-variate analysis, age over 60 years, NOTCH2 mutation, and any mutation of the NOTCH pathway (NOTCH2, NOTCH1, SPEN) were associated with shorter overall survival. Mutation of the NOTCH pathway retained an independent significance (P=0.029). In conclusion, a subset of patients with hepatitis C virus-positive diffuse large B-cell lymphoma displays a molecular signature of splenic marginal zone and has a worse clinical outcome.
UR - http://www.scopus.com/inward/record.url?scp=84964285656&partnerID=8YFLogxK
U2 - 10.3324/haematol.2014.116855
DO - 10.3324/haematol.2014.116855
M3 - Article
SN - 0390-6078
VL - 100
SP - 246
EP - 252
JO - Haematologica
JF - Haematologica
IS - 2
ER -
