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已发表论文
乙型肝炎病毒相关滤泡性淋巴瘤的临床风险分层及可改变的风险因素
Authors Deng Y , Jia Z, Zhang H, Zhang X, Liu L, Wang X, Song H, Zhang Z, Liu C, Zhang Q, Ma J
Received 3 June 2025
Accepted for publication 6 November 2025
Published 12 November 2025 Volume 2025:14 Pages 1293—1312
DOI https://doi.org/10.2147/ITT.S543117
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 2
Editor who approved publication: Professor Jadwiga Jablonska
Yuwei Deng,1 Zhenyuan Jia,1 Huilai Zhang,2 Xiaosan Zhang,3 Lihong Liu,4 Xianhuo Wang,2 Hongtao Song,5 Zirong Zhang,6 Caili Liu,6 Qingyuan Zhang,1 Jianli Ma7
1Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, People’s Republic of China; 2Department of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, Tianjin, People’s Republic of China; 3Department of Medical Oncology, Henan Cancer Hospital, Zhengzhou, Henan, People’s Republic of China; 4Department of Hematology, The Fourth Hospital of Hebei Medical University, Hebei Provincial Key Laboratory of Tumor Microenvironment and Drug Resistance, Shijiazhuang, Hebei, People’s Republic of China; 5Department of Pathology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, People’s Republic of China; 6Department of Hematology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, People’s Republic of China; 7Department of Radiation Oncology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, People’s Republic of China
Correspondence: Jianli Ma, Department of Radiation Oncology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, People’s Republic of China, Tel +86-18686837985, Email 601959@hrbmu.edu.cn Qingyuan Zhang, Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, People’s Republic of China, Tel +86-13313612989, Email 0566@hrbmu.edu.cn
Background: Hepatitis B virus (HBV) infection (surface antigen positive, HBsAg+) has been related to the increased risk in follicular lymphoma (FL). The further understanding of features in HBV-associated FL remains lacking.
Methods: We explored clinical risk factors in HBsAg-positive patients from multicentric clinical investigation retrospectively (n = 276) and integrated HBV-related factors into Follicular Lymphoma International Prognostic Index (FLIPI) scoring system for risk prediction. The methylation profiles in pre- and paired HBsAg+FL occurring progression of disease within 2 years (POD24) were determined using the Human Methylation 850K BeadChip platform. Bulk RNA sequencing was performed for gene expression in samples from the same patient and confirmed using MycCd19Cre C57BL/6J chimera mice.
Results: We found that HBsAg+ FL with a higher incidence of POD24. The high HBV-DNA load (> 105 copies/mL) was identified as a pivotal risk factor. HBsAg+ FL with the rapidly decreasing viral load showed lower incidence of POD24 than those without viral control (P = 0.026). Integrated risk stratification incorporating HBV-related clinical parameters based on FLIPI scoring systems had potential predictive value for high-risk patients (AUC = 0.616, P = 0.002). The methylation profiles in pre-POD24-HBsAg+FL and paired POD24-HBsAg+FL showed distinguished signatures of methylated KMT2A, EP300-AS1, ARID1B, MHC I class molecular genes related to tumor cells, and TNFRSF1A, LTA, IQCE genes related to immune cells. Of note, we confirmed that the crucial CXCR5 mRNA expression with specific methylated regions was inversely correlated to featured MYC mRNA expression as “trans” regulation in both POD24-HBsAg+FL and MycCd19Cre lymphoma model.
Conclusion: Integrated clinicopathological features into prediction system may provide precise risk stratification for HBV-positive FL. Modifiable DNA methylation acts as the potential targets for the combined treatment strategy to delay POD24 occurrence.
Plain Language Summary: Based on the retrospective clinical data from multiple clinical centers of China, we first present the clinical characteristics associated with chronic hepatitis B virus (HBV) infection and illustrated their prognostic roles in follicular lymphoma. We novelly integrated HBV-related risk factors into the canonical Follicular Lymphoma International Prognostic Index scoring. We revealed that modifiable genes methylation,especially in genes which regulated immune response, was associated with the early relapse of disease. The myelocytomatosis oncogene (MYC) is the driver for the aggressive progression of B-cell lymphoma in multiple clinical guidelines. Of note, we further confirmed that Chemokine C-X-C-Motif Receptor 5 (CXCR5) mRNA expression with specific methylated regions was inversely correlated to MYC mRNA expression during the disease progression, showing the potential promotion of immune activities on tumor progression. Our study provided the potential targets to delay the disease progression within 24 months (POD24) through reversing methylation modification in the further epigenetic molecular treatment.
Keywords: follicular lymphoma, hepatitis B virus, POD24, risk prediction, methylation, MYC, CXCR5
1Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, People’s Republic of China; 2Department of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, Tianjin, People’s Republic of China; 3Department of Medical Oncology, Henan Cancer Hospital, Zhengzhou, Henan, People’s Republic of China; 4Department of Hematology, The Fourth Hospital of Hebei Medical University, Hebei Provincial Key Laboratory of Tumor Microenvironment and Drug Resistance, Shijiazhuang, Hebei, People’s Republic of China; 5Department of Pathology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, People’s Republic of China; 6Department of Hematology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, People’s Republic of China; 7Department of Radiation Oncology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, People’s Republic of China
Correspondence: Jianli Ma, Department of Radiation Oncology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, People’s Republic of China, Tel +86-18686837985, Email 601959@hrbmu.edu.cn Qingyuan Zhang, Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, People’s Republic of China, Tel +86-13313612989, Email 0566@hrbmu.edu.cn
Background: Hepatitis B virus (HBV) infection (surface antigen positive, HBsAg+) has been related to the increased risk in follicular lymphoma (FL). The further understanding of features in HBV-associated FL remains lacking.
Methods: We explored clinical risk factors in HBsAg-positive patients from multicentric clinical investigation retrospectively (n = 276) and integrated HBV-related factors into Follicular Lymphoma International Prognostic Index (FLIPI) scoring system for risk prediction. The methylation profiles in pre- and paired HBsAg+FL occurring progression of disease within 2 years (POD24) were determined using the Human Methylation 850K BeadChip platform. Bulk RNA sequencing was performed for gene expression in samples from the same patient and confirmed using MycCd19Cre C57BL/6J chimera mice.
Results: We found that HBsAg+ FL with a higher incidence of POD24. The high HBV-DNA load (> 105 copies/mL) was identified as a pivotal risk factor. HBsAg+ FL with the rapidly decreasing viral load showed lower incidence of POD24 than those without viral control (P = 0.026). Integrated risk stratification incorporating HBV-related clinical parameters based on FLIPI scoring systems had potential predictive value for high-risk patients (AUC = 0.616, P = 0.002). The methylation profiles in pre-POD24-HBsAg+FL and paired POD24-HBsAg+FL showed distinguished signatures of methylated KMT2A, EP300-AS1, ARID1B, MHC I class molecular genes related to tumor cells, and TNFRSF1A, LTA, IQCE genes related to immune cells. Of note, we confirmed that the crucial CXCR5 mRNA expression with specific methylated regions was inversely correlated to featured MYC mRNA expression as “trans” regulation in both POD24-HBsAg+FL and MycCd19Cre lymphoma model.
Conclusion: Integrated clinicopathological features into prediction system may provide precise risk stratification for HBV-positive FL. Modifiable DNA methylation acts as the potential targets for the combined treatment strategy to delay POD24 occurrence.
Plain Language Summary: Based on the retrospective clinical data from multiple clinical centers of China, we first present the clinical characteristics associated with chronic hepatitis B virus (HBV) infection and illustrated their prognostic roles in follicular lymphoma. We novelly integrated HBV-related risk factors into the canonical Follicular Lymphoma International Prognostic Index scoring. We revealed that modifiable genes methylation,especially in genes which regulated immune response, was associated with the early relapse of disease. The myelocytomatosis oncogene (MYC) is the driver for the aggressive progression of B-cell lymphoma in multiple clinical guidelines. Of note, we further confirmed that Chemokine C-X-C-Motif Receptor 5 (CXCR5) mRNA expression with specific methylated regions was inversely correlated to MYC mRNA expression during the disease progression, showing the potential promotion of immune activities on tumor progression. Our study provided the potential targets to delay the disease progression within 24 months (POD24) through reversing methylation modification in the further epigenetic molecular treatment.
Keywords: follicular lymphoma, hepatitis B virus, POD24, risk prediction, methylation, MYC, CXCR5