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Genetic landscape of hepatitis B virus-associated diffuse large B-cell lymphoma.

ABSTRACT: Hepatitis B virus (HBV) infection is endemic in some parts of Asia, Africa, and South America and remains to be a significant public health problem in these areas. It is known as a leading risk factor for the development of hepatocellular carcinoma, but epidemiological studies have also shown that the infection may increase the incidence of several types of B-cell lymphoma. Here, by characterizing altogether 275 Chinese diffuse large B-cell lymphoma (DLBCL) patients, we showed that patients with concomitant HBV infection (surface antigen positive [HBsAg⁺]) are characterized by a younger age, a more advanced disease stage at diagnosis, and reduced overall survival. Furthermore, by whole-genome/exome sequencing of 96 tumors and the respective peripheral blood samples and targeted sequencing of 179 tumors from these patients, we observed an enhanced rate of mutagenesis and a distinct set of mutation targets in HBsAg⁺ DLBCL genomes, which could be partially explained by the activities of APOBEC and activation-induced cytidine deaminase. By transcriptome analysis, we further showed that the HBV-associated gene expression signature is contributed by the enrichment of genes regulated by BCL6, FOXO1, and ZFP36L1. Finally, by analysis of immunoglobulin heavy chain gene sequences, we showed that an antigen-independent mechanism, rather than a chronic antigenic simulation model, is favored in HBV-related lymphomagenesis. Taken together, we present the first comprehensive genomic and transcriptomic study that suggests a link between HBV infection and B-cell malignancy. The genetic alterations identified in this study may also provide opportunities for development of novel therapeutic strategies.

SUBMITTER: Ren W

PROVIDER: S-EPMC6063049 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Genetic landscape of hepatitis B virus-associated diffuse large B-cell lymphoma.

Ren Weicheng W Ye Xiaofei X Su Hong H Li Wei W Liu Dongbing D Pirmoradian Mohammad M Wang Xianhuo X Zhang Bo B Zhang Qiang Q Chen Longyun L Nie Man M Liu Yao Y Meng Bin B Huang Huiqiang H Jiang Wenqi W Zeng Yixin Y Li Wenyu W Wu Kui K Hou Yong Y Wiman Klas G KG Li Zhiming Z Zhang Huilai H Peng Roujun R Zhu Shida S Pan-Hammarström Qiang Q

Blood 20180315 24

Hepatitis B virus (HBV) infection is endemic in some parts of Asia, Africa, and South America and remains to be a significant public health problem in these areas. It is known as a leading risk factor for the development of hepatocellular carcinoma, but epidemiological studies have also shown that the infection may increase the incidence of several types of B-cell lymphoma. Here, by characterizing altogether 275 Chinese diffuse large B-cell lymphoma (DLBCL) patients, we showed that patients with ...[more]

PMID: 29545328

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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:BackgroundWhile the epidemiologic association between hepatitis B virus (HBV) infection and diffuse large B-cell lymphoma (DLBCL) is established, little is known about the pathological characteristics and outcome of DLBCL arising in patients with HBV infection.MethodsWe retrospectively studied a cohort of 420 patients with DLBCL for the incidence of HBV infection, and the clinicopathologic features and prognostic factors in HBsAg-positive DLBCL patients in China, a hepatitis B endemic area.ResultsIn our study, 127 (30.2%) patients were HBsAg-positive. HBsAg-positive DLBCL displayed a younger median onset age (50 vs. 54 years, P = 0.002), more frequent involvement of the spleen (19.7% vs. 6.1%, P < 0.001), less frequent involvement of the small and large intestine (2.3% vs. 11.2%, P = 0.003), more advanced disease (stage III/IV: 56.7% vs. 45.1%, P = 0.028), and lower expression rate of MYC (49.1% vs. 66.7%, P = 0.026). The median follow-up time was 61.9 months. Univariate analysis showed that there was no significant difference in overall survival (OS) between HBsAg-negative and -positive DLBCL (P = 0.577). In the HBsAg-positive DLBCL subgroup, age older than 60 years, advanced disease, elevated lactate dehydrogenase (LDH), spleen involvement, B symptoms (fever, night sweats, weight loss), and double expressers of MYC and BCL2 had a significantly worse outcome, and patients treated with R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) had a better prognosis. Multivariate analysis further confirmed that spleen involvement and rituximab use were independent prognostic factors in HBsAg-positive DLBCL patients.ConclusionsOur study indicates that HBsAg-positive DLBCL has unique clinicopathological features and independent prognostic factors. Moreover, under antiviral prophylaxis, the survival of DLBCL patients with HBV infections was comparable to that of HBV-negative patients, and the use of rituximab significantly improved OS in HBsAg-positive DLBCL patients.

Dataset Information

Genetic landscape of hepatitis B virus-associated diffuse large B-cell lymphoma.

Publications

Genetic landscape of hepatitis B virus-associated diffuse large B-cell lymphoma.

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