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

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-?B, 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.

SUBMITTER: Arcaini L

PROVIDER: S-EPMC4803124 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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

Arcaini Luca L Rossi Davide D Lucioni Marco M Nicola Marta M Bruscaggin Alessio A Fiaccadori Valeria V Riboni Roberta R Ramponi Antonio A Ferretti Virginia V VV Cresta Stefania S Casaluci Gloria Margiotta GM Bonfichi Maurizio M Gotti Manuel M Merli Michele M Maffi Aldo A Arra Mariarosa M Varettoni Marzia M Rattotti Sara S Morello Lucia L Guerrera Maria Luisa ML Sciarra Roberta R Gaidano Gianluca G Cazzola Mario M Paulli Marco M

Haematologica 20141107 2

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 ...[more]

PMID: 25381127

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Project description:ObjectiveThe purpose of this study was to determine the association between PD1 expression and the clinical prognosis of diffuse large B-cell lymphoma (DLBCL) co-occurring with hepatitis B virus (HBV) infection.MethodsA total of 165 patients presented with newly diagnosed and untreated DLBCL at the First Hospital of Jilin University, Changchun, China, between 2011.01 and 2014.12. Complete clinical information was available for 152 of these 165 patients. We retrospectively reviewed the results of HBV serum marker assays and the clinical information of these 152 DLBCL patients from our hospital database; eventually, only 51 patients were enrolled in this study, and these 51 patients received the PD1 test item.Results① The incidence of HBsAg prevalence was 13.2% (20/152) in this study; ② The incidence of PD1 expression in the HBsAg+ group was 4.3-fold higher than that in the HBsAg-group (40.0% vs 9.4%; P = 0.010); ③ The clinical information, including sex, age, clinical stage, IPI, molecular subtype and chemotherapy status, was analyzed between the HBsAg+ and HBsAg-groups, but there were no significant differences between the two groups; ④ The median OS and PFS of the patients in the HBsAg+ group were 36.5 months and 12 months, respectively; however, the median OS and PFS of patients in the HBsAg-group were not reached (P = 0.033) and 32 months (P = 0.049), respectively; and ⑤ The median OS and PFS of PD1-positive patients in the HBsAg+ group were the worst (24 months and 9 months, respectively), whereas the median OS and PFS of PD1-negative patients in the HBsAg-group were the best (not reached and 32 months, respectively).ConclusionsCompared with patients in the HBsAg-group, the incidence of PD1 expression was significantly higher in the HBsAg+ group, and the median OS and PFS times were the worst in PD1-positive patients in the HBsAg+ group. These results indicated that the dismal prognosis of patients with HBsAg+ may be related to the high rate of PD1 expression. Thus, a targeted PD1 treatment strategy may improve the prognosis of HBsAg+ DLBCL patients.

Project description:Objective:To determine the clinical features and survival difference of HBV related and Non-HBV related diffuse large B-cell lymphoma (DLBCL) and to evaluate the occurrence of HBV reactivation in DLBCL patients and related risk factors for HBV reactivation after R-CHOP therapy. Methods:A total of 246 patients diagnosed with CD20+ DLBCL were enrolled from June 2010 to June 2015. The medical records and survival data were analysed. Multivariate logistic regression analysis was used to identify predictors of HBV reactivation. Survival curves were performed by the Kaplan-Meier method. Results:Among patients enrolled, 80 patients were HBsAg sero-positive and 166 patients were HBsAg sero-negative. Findings showed that HBsAg sero-negative patients were significantly older than that of patients with HBsAg sero-positive (P?<? 0.001). Proportion of B symptom positive patients in HBsAg sero-positive were higher (p?=?0.002). Higher LDH level (P?=?0.019) and late Ann Arbor stage (P?=?0.010) were more often observed in patients with HBsAg sero-positive. The rate of complete response, partial response, stable disease and progress disease in HBsAg sero-negative group were 63.9, 16.9, 1.1 and 18.1%, respective, which is significantly higher than that in HBsAg sero-positive group (36.2, 18.8, 1.2 and 43.8%). Kaplan-Meier analysis showed that DLBCL patients with HBsAg sero-negative had better prognosis. In total, 17 patients showed HBV reactivation among 166 patients (10.2%) with HBsAg sero-negative after R-CHOP treatment, while a significant higher HBV reactivation 18.75% (9/48) in HBsAb negative group were observed, with 8.25% (8/97) patients in HBsAb level 10-100?U/mL group, and 0% patients in HBsAb level higher than 100?U/mL group. Multivariable analysis showed that serum HBsAb and serum HBcAb were independent risk factors for HBV reactivation in DLBCL patients. Conclusion:Our data revealed that characteristics and prognosis were significantly different between HBV related DLBCL than non-HBV related DLBCL patients. DLBCL patients with resolved hepatitis B are at a higher risk of developing HBV reactivation after R-CHOP chemotherapy compared with HBsAg-negative/HBcAb negative patients.

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

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

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