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. 2015 Feb;100(2):246-52.
doi: 10.3324/haematol.2014.116855. Epub 2014 Nov 7.

The NOTCH pathway is recurrently mutated in diffuse large B-cell lymphoma associated with hepatitis C virus infection

Luca Arcaini  1 , Davide Rossi  2 , Marco Lucioni  3 , Marta Nicola  4 , Alessio Bruscaggin  2 , Valeria Fiaccadori  4 , Roberta Riboni  3 , Antonio Ramponi  5 , Virginia V Ferretti  6 , Stefania Cresta  2 , Gloria Margiotta Casaluci  2 , Maurizio Bonfichi  6 , Manuel Gotti  6 , Michele Merli  7 , Aldo Maffi  4 , Mariarosa Arra  4 , Marzia Varettoni  6 , Sara Rattotti  6 , Lucia Morello  4 , Maria Luisa Guerrera  4 , Roberta Sciarra  4 , Gianluca Gaidano  2 , Mario Cazzola  8 , Marco Paulli  9
Affiliations

The NOTCH pathway is recurrently mutated in diffuse large B-cell lymphoma associated with hepatitis C virus infection

Luca Arcaini et al. Haematologica. 2015 Feb.

Abstract

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.

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Figures

Figure 1.
Figure 1.
Histological picture of a case of diffuse large B-cell lymphoma exhibiting a perifollicular growth pattern (A) (HE 20X) and consisting of cells with abundant clear cytoplasm (B) (Giemsa 40x), resembling monocytoid B cells, that is reminiscent of a marginal zone origin.
Figure 2.
Figure 2.
(A) Mutations of NOTCH genes in diffuse large B-cell lymphoma associated with hepatitis C virus infection (white: wild-type; red: mutations). (B) Percentages of diffuse large B-cell lymphoma cases harboring mutations in selected genes belonging to cellular pathways that are recurrently altered in splenic marginal zone lymphoma.
Figure 3.
Figure 3.
Comparison of NOTCH1 and NOTCH2 mutation diffuse large B-cell lymphoma with or without hepatitis C virus infection.
Figure 4.
Figure 4.
Overall survival of 46 patients with diffuse large B-cell lymphoma associated with hepatitis C virus infection according to mutational status of NOTCH pathway.
See this image and copyright information in PMC

References

    1. de Sanjose S, Benavente Y, Vajdic CM, et al. Hepatitis C and non-Hodgkin lymphoma among 4784 cases and 6269 controls from the International Lymphoma Epidemiology Consortium. Clin Gastroenterol Hepatol. 2008;6(4):451–458. - PMC - PubMed
    1. Mele A, Pulsoni A, Bianco E, et al. Hepatitis C virus and B-cell non-Hodgkin lymphomas: an Italian multicenter case-control study. Blood. 2003;102(3):996–999. - PubMed
    1. Saadoun D, Suarez F, Lefrere F, et al. Splenic lymphoma with villous lymphocytes, associated with type II cryoglobulinemia and HCV infection: a new entity? Blood. 2005; 105(1):74–76. - PubMed
    1. Hermine O, Lefrere F, Bronowicki JP, et al. Regression of splenic lymphoma with villous lymphocytes after treatment of hepatitis C virus infection. N Engl J Med. 2002;347(2):89–94. - PubMed
    1. Rossi D, Trifonov V, Fangazio M, et al. The coding genome of splenic marginal zone lymphoma: activation of NOTCH2 and other pathways regulating marginal zone development. J Exp Med. 2012; 209(9):1537–1551. - PMC - PubMed

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