乙型肝炎病毒S区基因突变对乙型肝炎病毒相关性肝细胞癌患者预后的影响研究

doi:10.12114/j.issn.1007-9572.2019.00.156

摘要/Abstract

摘要： 背景　我国肝癌发病率逐年上升，这主要与乙型肝炎病毒（HBV）感染流行有关，多项研究表明HBV基因突变与乙型肝炎病毒相关性肝细胞癌（HBV-HCC）患者发病密切相关，HBV S区基因突变与HBV-HCC患者术后预后的关系鲜有报道。目的　通过对HBV S区基因进行测序分析，分析一般资料及HBV S区基因突变位点与HBV-HCC患者预后的关系。方法　本研究于2007—2009年采集在河北医科大学第四医院行外科手术治疗的46例HBV-HCC患者的肝癌组织标本进行分析，提取DNA，针对HBV S区基因进行扩增和测序，鉴定出HBV S区基因的突变位点。记录患者的一般资料（年龄、性别、CHILD分级、基因型、肿瘤数目、门脉瘤栓、TNM分期、肿瘤大小）。分析一般资料及HBV S区基因突变位点与HBV-HCC患者术后预后的关系。结果　46例HBV-HCC患者的基因分型为25例B型、21例C型。不同门脉瘤栓、TNM分期、肿瘤大小的HBV-HCC患者3年生存率比较，差异有统计学意义（P<0.05）。共发现13个位点的突变频率>5％，其中529位点、735位点不同碱基HBV-HCC患者3年生存率比较，差异有统计学意义（P<0.05）。Cox比例风险模型分析结果显示，门脉瘤栓、529位点是HBV-HCC患者术后生存的独立影响因素（P<0.05）。结论　门脉瘤栓和HBV S区529位点被确定为是与HBV-HCC患者术后预后相关的独立危险因素，这一结果有助于鉴别预后不良的HBV-HCC患者，对于提高其生存期、改善其预后具有重要意义。

关键词: 乙型肝炎病毒；肝肿瘤；癌, 肝细胞；HBV S区；突变；预后

Abstract: Background　The incidence of hepatocellular carcinoma（HCC） in China is increasing year by year，which is mainly associated with the prevalence of hepatitis B virus（HBV） infection.Many studies have shown that HBV gene mutation is closely related to the pathogenesis of HBV-associated HCC.But there are few reports on the relationship between mutations in the S gene region of HBV and prognosis of patients with HBV-associated HCC.Objective　To investigate the relationships of clinical factors，and HBV S gene mutations （using sequencing analysis） with postoperative survival of
HBV-associated HCC patients.Methods　Participants were 46 cases of HBV-associated HCC who received surgical treatment in the Fourth Hospital of Hebei Medical University during 2007 to 2009.The genomic DNA was extracted from resected HCC tissues.HBV S gene was amplified and sequenced to detect mutations.General data〔age，sex，Child-Pugh score，genotype，number of tumor entities，portal vein tumor thrombus （PVTT），TNM classification，size of tumor〕 were collected.Relationships of general data，and HBV S gene mutations with the survival of the patients were analyzed.Results　 Of the participants，25 were found with HBV genotype B infection，and other 21 with HBV genotype C infection.Postoperative 3-year survival rates differed significantly by PVTT prevalence，TNM classification，and tumor size（P<0.05）．13 loci were identified with a mutation rate of higher than 5％.In particular，postoperative 3-year survival rates significantly varied by the mutations at the 529 and 735 locus（P<0.05）．Analysis with the Cox proportional hazards model found that PVTT and mutations at the 529 locus were independent influencing factors for postoperative survival（P<0.05）．Conclusion　PVTT prevalence and mutation at the 529 locus were identified as independent risk factors for postoperative survival in HBV-associated HCC patients，which may help to clinically identify such patients with poor prognosis，and may contribute to survival prolongation and prognosis improvement.

Key words: Hepatitis B virus；Liver neoplasms；Carcinoma, hepatocellular；S gene region of HBV；Mutation；Prognosis

吴忱思,赵乐,吴建华,等. 乙型肝炎病毒S区基因突变对乙型肝炎病毒相关性肝细胞癌患者预后的影响研究[J]. 中国全科医学, 2019, 22(15): 1807-1811. DOI: 10.12114/j.issn.1007-9572.2019.00.156.
WU Chensi,ZHAO Yue,WU Jianhua, et al. Mutations in the S Gene Region of Hepatitis B Virus and Postoperative Survival in Patients with Hepatitis B Virus-associated Hepatocellular Carcinoma　[J]. Chinese General Practice, 2019, 22(15): 1807-1811. DOI: 10.12114/j.issn.1007-9572.2019.00.156.

参考文献

［1］MCGLYNN K A，PETRICK J L，LONDON W T.Global epidemiology of hepatocellular carcinoma：an emphasis on demographic and regional variability［J］．Clin Liver Dis，2015，19（2）：223-238．DOI：10.1016/j.cld.2015.01.001.
［2］吕桂帅，陈磊，王红阳.我国肝癌研究的现状与前景［J］．生命科学，2015，27（3）：237-248．DOI：10.13376/j.cbls/2015034.
LYU G S，CHEN L，WANG H Y.Research progress and prospect of liver cancer in China［J］．Chinese Bulletin of Life Sciences，2015，27（3）：237-248．DOI：10.13376/j.cbls/2015034.
［3］WANG C J，ZHANG F B，FAN H Y，et al．Sequence polymorphisms of mitochondrial D-loop and hepatocellular carcinoma outcome［J］．Biochem Biophys Res Commun，2011，406（3）：493-496．DOI：10.1016/j.bbrc.2011.02.088.
［4］HIRAOKA A，KAWAMURA T，AIBIKI T，et al．Prognosis and therapy for ruptured hepatocellular carcinoma：problems with staging and treatment strategy［J］．Eur J Radiol，2015，84（3）：366-371．DOI：10.1016/j.ejrad.2014.11.038.
［5］TR PO C，CHAN H L Y，LOK A.Hepatitis B virus infection［J］．Lancet，2014，384（9959）：2053-2063．DOI：10.1016/s0140-6736（14）60220-8.
［6］POLLICINO T，CACCIOLA I，SAFFIOTI F，et al．Hepatitis B virus preS/S gene variants：pathobiology and clinical implications［J］．J Hepatol，2014，61（2）：408-417．DOI：10.1016/j.jhep.2014.04.041.
［7］LU F M，ZHUANG H.Management of hepatitis B in China［J］．Chin Med J，2009，122（1）：3-4.
［8］郝华，杨俊英，侯临平，等．乙型肝炎病毒基因分型研究新进展［J］．中国实用医刊，2016，43（16）：125-128．DOI：10.3760/cma.j.issn.1674-4756.2016.16.050.
HAO H，YANG J Y，HOU L P，et al．Research advances of hepatitis B virus genotypes［J］．Chinese Journal of Practical Medicine，2016，43（16）：125-128．DOI：10.3760/cma.j.issn.1674-4756.2016.16.050.
［9］LI H M，WANG J Q，WANG R，et al．Hepatitis B virus genotypes and genome characteristics in China［J］．World J Gastroenterol，2015，21（21）：6684-6697．DOI：10.3748/wjg.v21.i21.6684.
［10］ZHANG X，DING H G.Key role of hepatitis B virus mutation in chronic hepatitis B development to hepatocellular carcinoma［J］．World J Hepatol，2015，7（9）：1282-1286．DOI：10.4254/wjh.v7.i9.1282.
［11］LAMONTAGNE R J，BAGGA S，BOUCHARD M J.Hepatitis B virus molecular biology and pathogenesis［J］．Hepatoma Res，2016，2（7）：163．DOI：10.20517/2394-5079.2016.05.
［12］董绍斌，王富珍，张爽，等．原发性肝癌合并HBV感染者的HBV基因特征分析［J］．中华实验和临床病毒学杂志，2017，31（2）：92-97．DOI：10.3760/CMA.J.ISSN.1003-9279.2017.02.002.
DONG S B，WANG F Z，ZHANG S，et al．Sequence analysis of HBV in primary hepatomas patients infected with HBV［J］．Chinese Journal of Experimental and Clinical Virology，2017，31
（2）：92-97．DOI：10.3760/CMA.J.ISSN.1003-9279.2017.02.002.
［13］郑丹，邓伟，黄天壬，等．广西壮族自治区肝癌高发区HBV基因型、BCP/前C区突变与肝癌相关性的研究［J］．中华流行病学杂志，2015，36（7）：725-729．DOI：10.3760/cma.j.issn.0254-6450.2015.07.013.
ZHENG D，DENG W，HUANG T R，et al．Relationship between hepatitis B virus genotype，BCP/Pre-C region mutations and risk of hepatocellular carcinoma in Guangxi Zhuang Autonomous Region［J］．Chinese Journal of Epidemiology，2015，36（7）：725-729．DOI：10.3760/cma.j.issn.0254-6450.2015.07.013.
［14］AN P，XU J H，YU Y Y，et al．Host and viral genetic variation in HBV-related hepatocellular carcinoma［J］．Front Genet，2018，9：261．DOI：10.3389/fgene.2018.00261.
［15］HATAZAWA Y，YANO Y，OKADA R，et al．Quasispecies variant of pre-S/S gene in HBV-related hepatocellular carcinoma with HBs antigen positive and occult infection［J］．Infect Agents Cancer，2018，13：7．DOI：10.1186/s13027-018-0179-4.
［16］石仁芳，吴继周，万裴琦，等．广西肝癌高发区乙型肝炎病毒基本核心启动子区A1762T/G1764A双突变对肝癌家族聚集的影响［J］．中国全科医学，2015，18（5）：530-534．DOI：10.3969/j.issn.1007-9572.2015.05.011.
SHI R F，WU J Z，WAN P Q，et al．Effect of double mutation of basal core promoter A1762T/G1764A of hepatitis B virus on familial aggregation of primary liver cancer in area of Guangxi with high primary liver cancer incidence［J］．Chinese General Practice，2015，18（5）：530-534．DOI：10.3969/j.issn.1007-9572.2015.05.011.
［17］MAINI M K，GEHRING A J.The role of innate immunity in the immunopathology and treatment of HBV infection［J］．J Hepatol，2016，64（1 Suppl）：S60-70．DOI：10.1016/j.jhep.2016.01.028.
［18］SUGIYAMA M，MIZOKAMI M.Hepatitis B virus genotype and the mutation related to clinical outcome［J］．Nippon Rinsho，2015，73（Suppl 9）：377-381.
［19］荣义辉，辛绍杰.乙型肝炎病毒S区基因变异研究进展［J］．肝脏，2013，18（11）：779-781．DOI：10.14000/j.cnki.issn.1008-1704.2013.11.001.
［20］YE Q，SHANG S Q，LI W.A new vaccine escape mutant of hepatitis B virus causes occult infection［J］．Hum Vaccin Immunother，2015，11（2）：407-410．DOI：10.4161/21645515.2014.994461.
［21］STICCHI L，CALIGIURI P，CACCIANI R，et al．Epidemiology of HBV S-gene mutants in the Liguria Region，Italy：implications for surveillance and detection of new escape variants［J］．Hum Vaccin Immunother，2013，9（3）：568-571.
［22］CHOI Y M，LEE S Y，KIM B J.Naturally occurring hepatitis B virus reverse transcriptase mutations related to potential antiviral drug resistance and liver disease progression［J］．World J Gastroenterol，2018，24（16）：1708-1724．DOI：10.3748/wjg.v24.i16.1708.
［23］WANG L H，HUANG W Y，LAI M D，et al．Aberrant cyclin A expression and centrosome overduplication induced by hepatitis B virus pre-S2 mutants and its implication in hepatocarcinogenesis［J］．Carcinogenesis，2012，33（2）：466-472．DOI：10.1093/carcin/bgr296.
［24］GWAK G Y，LEE D H，MOON T G，et al．The correlation of hepatitis B virus pre-S mutation with cellular oxidative DNA damage in hepatocellular carcinoma［J］．Hepatogastroenterology，2008，55（88）：2028-2032.
［25］李萍，王丽，胡蓉，等.血清纤维化标志物和肝功能指标在慢性乙型肝炎患者肝纤维化诊断中的价值［J］.疑难病杂志，2017，16（6）：575-578，583. DOI：10.3969/j.issn.1671-6450.2017.06.009.
LI P，WANG L，HU R，et al.The applications of serum fibrosis index and liver function in patients with chronic hepatitis B and its diagnostic value in liver fibrosis［J］. Chinese Journal of Difficult and Complicated Cases，2017，16（6）：575-578，583. DOI：10.3969/j.issn.1671-6450.2017.06.009.