The NOTCH pathway is recurrently mutated in diffuse large B-cell lymphoma associated with hepatitis C virus infection.
Hepatitis C virus has been found to be associated with B-cell non-Hodgkin lymphomas, mostly marginal zone lymphomas 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 lymphoma. 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 univariate 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.
Department of Molecular Medicine, University of Pavia Department of Hematology Oncology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico San Matteo, Pavia luca.arcaini@unipv.it.
Luca
L
Arcaini
Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara.
Davide
D
Rossi
Department of Pathology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico San Matteo, Pavia.
Marco
M
Lucioni
Department of Molecular Medicine, University of Pavia.
Marta
M
Nicola
Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara.
Alessio
A
Bruscaggin
Department of Molecular Medicine, University of Pavia.
Valeria
V
Fiaccadori
Department of Pathology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico San Matteo, Pavia.
Roberta
R
Riboni
Division of Pathology, Department of Health Science, Amedeo Avogadro University of Eastern Piedmont, Novara.
Antonio
A
Ramponi
Department of Hematology Oncology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico San Matteo, Pavia.
Virginia V
VV
Ferretti
Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara.
Stefania
S
Cresta
Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara.
Gloria Margiotta
GM
Casaluci
Department of Hematology Oncology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico San Matteo, Pavia.
Maurizio
M
Bonfichi
Department of Hematology Oncology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico San Matteo, Pavia.
Manuel
M
Gotti
Division of Hematology, Ospedale di Circolo e Fondazione Macchi, University of Insubria, Varese, Italy.
Michele
M
Merli
Department of Molecular Medicine, University of Pavia.
Aldo
A
Maffi
Department of Molecular Medicine, University of Pavia.
Mariarosa
M
Arra
Department of Hematology Oncology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico San Matteo, Pavia.
Marzia
M
Varettoni
Department of Hematology Oncology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico San Matteo, Pavia.
Sara
S
Rattotti
Department of Molecular Medicine, University of Pavia.
Lucia
L
Morello
Department of Molecular Medicine, University of Pavia.
Maria Luisa
ML
Guerrera
Department of Molecular Medicine, University of Pavia.
Roberta
R
Sciarra
Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara.
Gianluca
G
Gaidano
Department of Molecular Medicine, University of Pavia Department of Hematology Oncology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico San Matteo, Pavia.
Mario
M
Cazzola
Department of Molecular Medicine, University of Pavia Department of Pathology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico San Matteo, Pavia.
Marco
M
Paulli
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics; D004268:DNA-Binding Proteins; D005260:Female; D005500:Follow-Up Studies; D016174:Hepacivirus / Q000302:isolation & purification; D006526:Hepatitis C / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000821:virology; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000821:virology; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D060787:Neoplasm Grading; D009364:Neoplasm Recurrence, Local / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000821:virology; D009687:Nuclear Proteins / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011379:Prognosis; D016601:RNA-Binding Proteins; D051881:Receptor, Notch1 / Q000235:genetics*; D051883:Receptor, Notch2 / Q000235:genetics*; D015996:Survival Rate
D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; C497761:NOTCH1 protein, human; C497764:NOTCH2 protein, human; D009687:Nuclear Proteins; D016601:RNA-Binding Proteins; D051881:Receptor, Notch1; D051883:Receptor, Notch2; C476510:SPEN protein, human