乙型肝炎病毒的區隔演變對肝細胞癌的預後有不同的貢獻

StephenW

Compartmentalized evolution of hepatitis B virus contributes differently to the prognosis of hepatocellular carcinoma
Jianhua Yin  1 , Xi Chen  1 , Nan Li  2 , Xuewen Han  2 , Wenbin Liu  1 , Rui Pu  1 , Ting Wu  1 , Yibo Ding  1 , Hongwei Zhang  1 , Jun Zhao  2 , Xue Han  3 , Hongyang Wang  4   5 , Shuqun Cheng  2   4   5 , Guangwen Cao  1   4   5
Affiliations
Affiliations

    1
    Department of Epidemiology, Faculty of Navy Medicine, Second Military Medical University, Shanghai, China.
    2
    Department of Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.
    3
    Division of Chronic Diseases, Center for Disease Control and Prevention of Yangpu District, Shanghai, China.
    4
    Key Laboratory of Signaling Regulation and Targeting Therapy of Liver Cancer, Ministry of Education, Shanghai, China.
    5
    Shanghai Key Laboratory of Hepatobiliary Tumor Biology, Shanghai, China.

    PMID: 33247709 DOI: 10.1093/carcin/bgaa127

Abstract

Serum hepatitis B virus (HBV) mutations can predict hepatocellular carcinoma (HCC) occurrence. We aimed to clarify if HBV evolves synchronously in the sera, adjacent liver, and tumors and predict HCC prognosis equally. A total of 203 HBV-positive HCC patients with radical hepatectomy in Shanghai, China during 2011-2015 were enrolled in this prospective study. Quasispecies complexity (QC) in HBV core promoter region was assessed using clone-based sequencing. We performed RNA-sequencing on tumors and paired adjacent tissues of another 15 HCC patients and analyzed it with 3 public datasets containing 127 samples. HBV QC was positively correlated to APOBEC3s' expression level (r=0.28, p<0.001), higher in the adjacent tissues than in the tumors (p=6.50e-3), and higher in early tumors than in advanced tumors (p=0.039). The evolutionary distance between the sera-derived HBV strains and the tumor-derived ones was significantly longer than that between the sera-derived ones and the adjacent tissue-derived ones (p<0.001). Multivariate Cox regression analyses indicated that high HBV QC in the sera predicted an unfavorable overall survival (OS) (p=0.002) and recurrence-free survival (RFS) (p=0.004) in HCC; whereas it in the tumors predicted a favorable RFS (p<0.001), respectively. APOBECs-related HBV mutations including G1764A were more frequent in the sera than in the adjacent tissues. High-frequent A1762T/G1764A in the sera predicted an unfavorable RFS (p<0.001); whereas it in the tumors predicted a favorable RFS (p=0.035). In conclusion, HBV evolves more advanced in the sera than in the tumors. HBV QC and A1762T/G1764A in the sera and tumors have contrary prognostic effects in HCC.

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StephenW

乙型肝炎病毒的區隔演變對肝細胞癌的預後有不同的貢獻
尹建華1，陳晨1，南里2，韓雪雯2，劉文彬1，普瑞1，吳婷1，丁一波1，張宏偉1，趙軍2，薛漢3，王洪陽4 5，舒群程2 4 5，曹光文1 4 5
隸屬關係
隸屬關係

    1個
    第二軍醫大學海軍醫學院流行病學系，上海
    2
    第二軍醫大學東方肝膽外科醫院外科
    3
    中國上海市楊浦區疾病預防控制中心慢性病科。
    4
    肝癌信號調節與靶向治療教育部重點實驗室，上海
    5
    上海市肝膽腫瘤生物學重點實驗室，上海

    PMID：33247709 DOI：10.1093 / carcin / bgaa127

抽象

血清乙型肝炎病毒（HBV）突變可以預測肝細胞癌（HCC）的發生。我們旨在闡明HBV是否在血清，鄰近肝臟和腫瘤中同步發展，並平等地預測HCC的預後。這項前瞻性研究納入了2011年至2015年間在中國上海進行的203例HBV陽性肝癌根治性肝切除術患者。使用基於克隆的測序評估了HBV核心啟動子區域的準物種複雜性（QC）。我們對另外15例HCC患者的腫瘤和配對的相鄰組織進行了RNA測序，並使用包含127個樣本的3個公共數據集對其進行了分析。 HBV QC與APOBEC3的表達水平呈正相關（r = 0.28，p <0.001），在鄰近組織中高於腫瘤（p = 6.50e-3），在早期腫瘤中高於晚期腫瘤（p = 0.039）。血清來源的HBV毒株和腫瘤來源的毒株之間的進化距離明顯長於血清來源的HBV毒株和鄰近的組織來源的毒株之間的進化距離（p <0.001）。多元Cox回歸分析表明，血清中高HBV QC預測肝癌的總體生存率（OS）（p = 0.002）和無復發生存率（RFS）（p = 0.004）。而它在腫瘤中的預測RFS分別良好（p <0.001）。包括G1764A在內的APOBECs相關的HBV突變在血清中比在相鄰組織中更為頻繁。血清中高頻率的A1762T / G1764A預測RFS不良（p <0.001）；而它在腫瘤中預示著良好的RFS（p = 0.035）。總之，乙肝病毒在血清中的發展比在腫瘤中發展的要先進。血清和腫瘤中的HBV QC和A1762T / G1764A在HCC中具有相反的預後作用。

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