福建省慢性HBV感染者HBV基因S区、基本核心启动子区和前C区基因变异特征分析

为研究福建省慢性HBV感染者HBV基因多样性及变异规律,了解该人群HBV-DNA的病毒学特征。收集慢性HBV感染者血清标本,通过巢式PCR法扩增其HBV基因序列,比对NCBI数据库中标准基因型序列,分析HBV基因S区,基本核心启动子区(BCP)及前C区的序列变异情况,并对这些变异可能造成的病毒抗原表达,疫苗逃逸,患者病症改变等情况进行探讨。最终成功扩增82例HBV全长基因序列,其中B基因型56例,C基因型26例。基因组特定功能区序列分析发现慢性HBV感染者HBV基因在S区(23.2%)、BCP区(61.0%)和前C区(29.3%)均出现了不同程度的变异。其中主蛋白(HBsAg)主要抗原决定簇a决定簇45.8%位点出现了变异,这些变异位点中包括与肝炎重症化及免疫逃逸密切相关的位点(aa126、aa129、aa145等)。位点G1896A(19.5%),G1764A(11.0%)和A1762T(9.8%)依然是BCP/前C区的主要突变位点。而位点A1752G(25.6%)高突变率的出现在BCP区应引起关注。此外位点G1764A(χ~2=5.742,P=0.030)、A1896G(χ~2=14.392,P=0.000)以及A1762T/G1764A(χ~2=7.289,P=0.012)的突变更容易发生在HBeAg阴性的样品中;而位点A1846T(χ~2=11.882,P=0.003)、A1762T(χ~2=6.561,P=0.038)和A1896G(χ~2=6.958,P=0.030)的突变与HBV-DNA的病毒载量存在一定相关性。总之,福建省慢性HBV感染者在HBV不同基因功能区域均存在不同程度的变异,一些与HBeAg表达情况、HBV-DNA载量、疫苗免疫逃避及肝细胞癌发生具有相关联的变异位点已经出现,BCP区A1752G位点的高频率出现应值得关注,对于这些变异位点的患者应加强监测。     

原发性肝癌患者乙型肝炎病毒前C区联合基本核心启动子变异的分析

目的:研究原发性肝癌患者乙型肝炎病毒前C区联合基本核心启动子变异情况及与基因型的关系.方法:收集乙型肝病毒感染者血清132份,HBV DNA均阳性,用半巢式聚合酶链反应扩增HBV前C及c基因部分片段,产物纯化后直接测序,检测前C A1896联合BCP T1762/A1764变异.用S基因PCR-RFLP方法确定HBV基因型.结果:乙型肝炎病毒前C区联合基本核心启动子变异在原发性肝癌组的阳性率为41.18%(14/34),显著高于慢性肝病组的11.22%(11/98)(P<0.01).前CA1896联合BCP T1762/A1764变异在B基因型检出率与C基因型相比,差异无显著性(P>0.05).结论:乙型肝炎病毒前C区联合基本核心启动子变异与原发性肝癌关系密切,与基因型无相关性.     

综述:乙型肝炎病毒所致非可控性炎症恶性转化的可能机制

肝细胞癌(HCC)占我国大陆地区恶性肿瘤死亡原因的第二位,主要由乙型肝炎病毒(HBV)慢性感染所致.人类白细胞Ⅱ类抗原遗传多态性与HBV感染的慢性化有关.HBV与免疫系统相互作用导致的非可控性炎症是HBV进化和HCC发生的必要因素.持续的、非充分的抗病毒免疫对HBV变异有选择作用.在炎症促癌过程中病毒和肝细胞基因组均经历了"变异-选择-适应"的进化过程.HBV变异不但能预测HCC的发生,而且具有促癌功能.HBV在肝细胞基因组中整合,尤其是羧基端截短型X基因的整合不但促进HCC的发生和转移,而且抵抗抗病毒治疗.明确HBV致癌机制可为降低和推迟HCC的发生和转移奠定基础.     

乙肝病毒前C区变异与其真核表达的研究进展

乙型肝炎病毒（HBV）变异与乙型肝炎病情的发展、对该疾病病情的监测等关系密切。其中,HBV前C区基因变异可使HBeAg产生异常的表达,并对HBV基因组的复制也有一定的影响。现就对HBV前C区基因常见变异及其生物学意义,及其真核表达模型构建相关因素等方面进行综述。     

乙型肝炎病毒所致非可控性炎症恶性转化的可能机制

肝细胞癌(HCC)占我国大陆地区恶性肿瘤死亡原因的第二位,主要由乙型肝炎病毒(HBV)慢性感染所致.人类白细胞Ⅱ类抗原遗传多态性与HBV感染的慢性化有关.HBV与免疫系统相互作用导致的非可控性炎症是HBV进化和HCC发生的必要因素.持续的、非充分的抗病毒免疫对HBV变异有选择作用.在炎症促癌过程中病毒和肝细胞基因组均经历了"变异-选择-适应"的进化过程.HBV变异不但能预测HCC的发生,而且具有促癌功能.HBV在肝细胞基因组中整合,尤其是羧基端截短型X基因的整合不但促进HCC的发生和转移,而且抵抗抗病毒治疗.明确HBV致癌机制可为降低和推迟HCC的发生和转移奠定基础.     

乙型肝炎病毒RT区变异及其与基因型分布的关系

目的：探讨大样本乙型肝炎病毒（HBV）感染患者RT区耐药位点变异的流行情况,及各耐药位点变异与HBV基因型的关系。方法：采用P区测序法对1117例慢性乙型肝炎患者的血清病毒进行P区测序、进化树分型。结果：RT区耐药位点变异发生率与基因型关系密切,在基因型C患者中的变异发生率远远高于基因型B患者（P=O．000）。Rt180、rtM204V、rtM204I、rt181、rt213位点变异均与基因型c有关（P〈O．05）。主要的三种变异类型rt180＋rtM204V、rtM204I、rt180＋rtM204I间基因型分布存在显薯差异（P=0．003）。不同HBeAg状态下,耐药变并的发生有显著差并（P=O．020）,特别是rt181和rt236位点变畀。结论：HBV基因型影响RT区耐药变异发生率及变异类型。且耐药变异发生率也与HBeAg状态有关。     

乙肝病毒感染与肝细胞癌

原发性肝细胞癌(hepatocellular carcinoma,HCC)是严重威胁人类健康的恶性肿瘤之一.HCC患者中1/3有慢性乙肝病史.目前研究已经证实,乙肝病毒(hepatitis B virus,HBV)感染是HCC发生的最危险因素.HBV致癌机制尚未明确,可能涉及病毒与宿主及环境的多阶段、多机制复杂过程.目前研究认为一些HBV相关的因素可能与HCC发生有关,如HBsAg状态、HBV DNA载量、HBV DNA基因型、前核心区和核心启动子区突变等.本文就目前一些流行病学因素及分子因素研究阐述如下.     

BRCA1基因启动子区SNPs与散发性乳腺癌易感性的相关研究（英文）

目的：探讨BRCA1基因启动子区rs11655505、rs73625095位点单核苷酸多态性与散发性乳腺癌易感性的关系。方法：采用ASA-PCR方法对200例乳腺癌患者（均经病理确诊）及200例正常女性BRCA1基因启动子区rs11655505（A/G）、rs73625095（A/G）位点单核苷酸多态性（SNP）进行分析,并将其PCR产物进行测序。结果：乳腺癌患者BRCA1基因启动子区rs11655505位点的A/G基因型频率为75%,显著高于正常人的40%;A/A基因型频率为7%,G/G基因型频率为18%,分别低于正常人的30%、30%。此位点的A或G等位基因在乳腺癌病例组及对照组中均无差别（x2=2.427,P=0.119）;rs73625095位点的A/G基因型频率为68%,显著高于正常人的15%;G/G基因型频率为32%,低于正常人的84%;乳腺癌病例组中BRCA1基因启动子区rs11655505、rs73625095位点的A/G基因型与淋巴结转移与否相比,差别均有统计学意义（x2=7.321,P=0.026、x2=4.782,P=0.029）。结论：BRCA1基因rs11655505位点、rs73625095位点的A/G基因型可能与散发性乳腺癌的发生相关,而且与有无发生淋巴结转移密切相关。rs73625095位点A和G等位基因可能为散发性乳腺癌发生的遗传危险因素。     

《细胞》：科学家为近百种“超级增强子”编制目录

据物理学家组织网10月10日报道。最近,美国怀特黑德生物医学研究所科学家发现了一套称为”超级增强子”的基因调控器,能控制、影响人类和小鼠的大量细胞型。研究人员指出,超级增强子富集在基因组的变异区,而这些变异区与多种疾病谱系密切相关。所以它们最终可能在疾病诊断与治疗方面发挥重要作用。相关论文在线发表于当天的《细胞》杂志网站上。     

DNMT1错义突变与神经管畸形易感性的相关性研究

DNMT1(DNA(cytosine-5)-methyltransferase 1)在神经管的闭合过程中发挥重要作用,已有研究表明,DNMT1敲除的小鼠会出现神经管畸形(neural tube defects,NTDs)的表型.为了进一步探索DNMT1基因错义突变与神经管畸形发生的相关性,本研究对来自中国汉族人群的101例神经管畸形患者血液样本和171例正常对照血液样本中提取的基因组DNA进行了全基因组测序.在这些病例的DNM T1基因上一共检测到了5个病例特有的错义突变,其中c.2626G＞A和c.4381C＞T突变在不同物种间高度保守,并且c.4381C＞T突变在公共数据库中没有记录.蛋白免疫印迹实验显示c.290A＞G,c.358G＞C,c.410C＞G,c.2626G＞A和c.4381C＞T这5个突变都使DNMT1蛋白表达量下调.免疫荧光实验显示这5个突变不影响DNMT1蛋白的核定位.我们的研究表明病例样本中DNMT1上鉴定到的5个病例特有的错义突变可能通过下调DNMT1的蛋白表达量而导致神经管畸形的发生.     

HLA-DP Polymorphisms Affect the Outcomes of Chronic Hepatitis B Virus Infections,Possibly through Interacting with Viral Mutations

Genetic polymorphisms of HLA-DP have been associated with hepatitis B virus (HBV) persistence. We aimed to determine the effect of HLA-DP polymorphisms on the generation of HBV mutations and their interactions on the outcomes of HBV infection. rs3077, rs3135021, rs9277535, and rs2281388 were genotyped in 1,342 healthy controls, 327 HBV clearance subjects, and 2,736 HBV-positive subjects, including 1,108 hepatocellular carcinoma (HCC) patients, using quantitative PCR. HBV mutations were determined by sequencing. Multiplicative interactions of HLA-DP polymorphisms and viral mutations were assessed by multivariate logistic regression. rs3077 (from subjects with genotype CT combined with those from subjects with genotype TT [CT+TT] versus CC), rs3135021 (GA+AA versus GG), rs9277535 (GA+AA versus GG), and rs2281388 (CC versus CT+TT) significantly decreased HBV persistence. This effect was found only in genotype B HBV-infected subjects compared to HBV clearance subjects. HLA-DP polymorphisms promoting HBV clearance were associated with a lower prevalence of mutations increasing HCC risk (C1653T, T1674C/G, A1846T, G1896A and pre-S2 mutations and pre-S deletion in genotype C) and a higher prevalence of mutations decreasing HCC risk (G1652A, T1673C, T1674C, G1719T, G1730C, and G1799C in genotype B and A1727T in genotype C). Significant effects of viral mutations on cirrhosis and HCC were selectively evident in those with HLA-DP polymorphisms promoting HBV persistence. The interactions of C1653T, T1674C/G, and G1896A mutations with HLA-DP polymorphisms promoting HBV clearance significantly decreased cirrhosis risk. The interaction of rs9277535 AA with the T1674C/G or G1719T mutation in genotype C significantly decreased HCC risk. In conclusion, HLA-DP polymorphisms affect genotype B HBV clearance, regulate immune selection of viral mutations, and influence cirrhosis and HCC risks contributed by HBV mutations.     

Association of Hepatitis B Virus Pre-S Deletions with the Development of Hepatocellular Carcinoma in Qidong,China

Background/Aim

To investigate the roles of mutations in pre-S and S regions of hepatitis B virus (HBV) on the progression of hepatocellular carcinoma (HCC) in Qidong, China.

Methods

We conducted an age matched case-control study within a cohort of 2387 male HBV carriers who were recruited from August, 1996. The HBV DNA sequence in pre-S/S regions was successfully determined in 96 HCC cases and 97 control subjects. In addition, a consecutive series of samples from 11 HCC cases were employed to evaluate the pre-S deletion patterns before and after the occurrence of HCC.

Results

After adjustment for age, history of cigarette smoking and alcohol consumption, HBeAg positivity, pre-S deletions, pre-S2 start codon mutations, and T53C mutation were significantly associated with HCC, showing adjusted odds ratios (ORs) from 1.914 to 3.199. HCC patients also had a lower frequency of T31C mutation in pre-S2 gene, compared with control subjects (0.524; 95% CI 0.280-0.982). HBV pre-S deletions were clustered mainly in the 5′ end of pre-S2 region. Multivariate analysis showed that pre-S deletions and pre-S2 start codon mutations were independent risk factors for HCC. The OR (95% CI) were 2.434 (1.063–5.573) and 3.065 (1.099–8.547), respectively. The longitudinal observation indicated that the pre-S deletion mutations were not acquired at the beginning of HBV infection, but that the mutations occurred during the long course of liver disease.

Conclusion

Pre-S deletions and pre-S2 start codon mutations were independently associated with the development of HCC. The results also provided direct evidence that pre-S deletion mutations were not acquired from the beginning of infection but arose de novo during the progression of liver disease.     

Pre-S Deletion and Complex Mutations of Hepatitis B Virus Related to Young Age Hepatocellular Carcinoma in Qidong,China

Background/Aim

To investigate the roles of biomedical factors, hepatitis B virus (HBV) DNA levels, genotypes, and specific viral mutation patterns on the progression of hepatocellular carcinoma (HCC) patients below 40 years of age in Qidong, China.

Methods

We conducted a case-control study within a cohort of 2387 male HBV carriers who were recruited from August, 1996. The HBV DNA sequence was determined in 49 HCC and 90 chronic hepatitis (CH) patients below 40 years of age. Mutation exchanges during follow-up in 32 cases were compared with 65 controls with paired serum samples. In addition, a consecutive series of samples from 14 HCC cases were employed to compare the sequences before and after the occurrence of HCC.

Results

After adjustment for age, history of cigarette smoking and alcohol consumption, HBeAg positive, HBV DNA levels ≥4.00 log₁₀ copies/mL, pre-S deletion, T1762/A1764 double mutations, and T1766 and/or A1768 mutations were associated with risk of young age HCC. Moreover, the presence of an increasing number of HCC-related mutations (pre-S deletion, T1762/A1764, and T1766 and/or A1768 mutations) was associated with an increased risk of young age HCC. Paired samples analysis indicated that the increased HCC risk for at-risk sequence mutations were attributable to the persistence of these mutations, but not a single time point mutation. The longitudinal observation demonstrated a gradual combination of pre-S deletion, T1762/A1764 double mutations, and T1766 and/or A1768 mutations during the development of HCC.

Conclusion

High HBV DNA levels and pre-S deletion were independent risk factors of young age HCC. Combination of pre-S deletion and core promoter mutations increased the risk and persistence of at-risk sequence mutations is critical for HCC development.     

Genotype-specific genomic markers associated with primary hepatomas, based on complete genomic sequencing of hepatitis B virus

We aimed to identify genomic markers in hepatitis B virus (HBV) that are associated with hepatocellular carcinoma (HCC) development by comparing the complete genomic sequences of HBVs among patients with HCC and those without. One hundred patients with HBV-related HCC and 100 age-matched HBV-infected non-HCC patients (controls) were studied. HBV DNA from serum was directly sequenced to study the whole viral genome. Data mining and rule learning were employed to develop diagnostic algorithms. An independent cohort of 132 cases (43 HCC and 89 non-HCC) was used to validate the accuracy of these algorithms. Among the 100 cases of HCC, 37 had genotype B (all subgenotype Ba) and 63 had genotype C (16 subgenotype Ce and 47 subgenotype Cs) HBV infection. In the control group, 51 had genotype B and 49 had genotype C (10 subgenotype Ce and 39 subgenotype Cs) HBV infection. Genomic algorithms associated with HCC were derived based on genotype/subgenotype-specific mutations. In genotype B HBV, mutations C1165T, A1762T and G1764A, T2712C/A/G, and A/T2525C were associated with HCC. HCC-related mutations T31C, T53C, and A1499G were associated with HBV subgenotype Ce, and mutations G1613A, G1899A, T2170C/G, and T2441C were associated with HBV subgenotype Cs. Amino acid changes caused by these mutations were found in the X, envelope, and precore/core regions in association with HBV genotype B, Ce, and Cs, respectively. In conclusion, infections with different genotypes of HBV (B, Ce, and Cs) carry different genomic markers for HCC at different parts of the HBV genome. Different HBV genotypes may have different virologic mechanisms of hepatocarcinogenesis.     

Associations of pri-miR-34b/c and pre-miR-196a2 Polymorphisms and Their Multiplicative Interactions with Hepatitis B Virus Mutations with Hepatocellular Carcinoma Risk

Background

Genetic polymorphisms of pri-miR-34b/c and pre-miR-196a2 have been reported to be associated with the susceptibility to cancers. However, the effect of these polymorphisms and their interactions with hepatitis B virus (HBV) mutations on the development of hepatocellular carcinoma (HCC) remains largely unknown. We hypothesized that these polymorphisms might interact with the HBV mutations and play a role in hepatocarcinogenesis.

Methods

Pri-miR-34b/c rs4938723 (T>C) and pre-miR-196a2 rs11614913 (T>C) were genotyped in 3,325 subjects including 1,021 HBV-HCC patients using quantitative PCR. HBV mutations were determined by direct sequencing. Contributions of the polymorphisms and their multiplicative interactions with gender or HCC-related HBV mutations to HCC risk were assessed using multivariate regression analyses.

Results

rs4938723 CC genotype was significantly associated with HCC risk compared to HBV natural clearance subjects, adjusted for age and gender (adjusted odds ratio [AOR] = 2.01, 95% confidence interval [CI] = 1.16–3.49). rs4938723 variant genotypes in dominant model significantly increased HCC risk in women, compared to female healthy controls (AOR = 1.85, 95% CI = 1.20–2.84) or female HCC-free subjects (AOR = 1.62, 95% CI = 1.14–2.31). rs4938723 CC genotype and rs11614913 TC genotype were significantly associated with increased frequencies of the HCC-related HBV mutations T1674C/G and G1896A, respectively. rs11614913 was not significantly associated with HCC risk, but its CC genotype significantly enhanced the effect of rs4938723 in women. In multivariate regression analyses, rs4938723 in dominant model increased HCC risk (AOR = 1.62, 95% CI = 1.05–2.49), whereas its multiplicative interaction with C1730G, a HBV mutation inversely associated with HCC risk, reduced HCC risk (AOR = 0.34, 95% CI = 0.15–0.81); rs11614913 strengthened the G1896A effect but attenuated the A3120G/T effect on HCC risk.

Conclusions

rs4938723 might be a genetic risk factor of HCC but its effect on HCC is significantly affected by the HBV mutations. rs11614913 might not be a HCC susceptible factor but it might affect the effects of the HBV mutations or rs4938723 on HCC risk.     

Naturally Occurring Precore/Core Region Mutations of Hepatitis B Virus Genotype C Related to Hepatocellular Carcinoma

Previous studies have proved the presence of several distinct types of mutations in hepatitis B virus (HBV) infections, which are related to the progression of liver disease. However, few reports have detailed the mutation frequencies and mutation patterns in the precore/core (preC/C) region, which are based on the clinical status and HBeAg serostatus. Our aim in this study is to investigate the relationships between the preC/C mutations and clinical severity or HBeAg serostatus from patients chronically infected with HBV genotype C. A total of 70 Korean chronic patients, including 35 with hepatocellular carcinoma (HCC), participated in this study. HBV genotyping and precore/core mutations were analyzed by direct sequencing. All patients were confirmed to have genotype C infections. Mutations in the C region were distributed in a non-random manner. In particular, mutations in the MHC class II restricted region were found to be significantly related to HCC. Six (preC-W28*, C-P5H/L/T, C-E83D, C-I97F/L, C-L100I and C-Q182K/*) and seven types (preC-W28*, preC-G29D, C-D32N/H, C-E43K, C-P50A/H/Y, C-A131G/N/P and C-S181H/P) of mutations in the preC/C region were found to be related to HCC and to affect the HBeAg serostatus, respectively. In conclusion, our data indicated that HBV variants in the C region, particularly in the MHC class II restricted region, may contribute to the progress of HCC in chronic patients infected with genotype C. In addition, we found several distinct preC/C mutations in the Korean chronic cohort, which affect the clinical status of HCC and HBeAg serostatus of patients infected with genotype C.     

PCR—DGGE法研究葡萄糖-6-磷酸脱氢酶缺乏症基因突变

目的：应用PCR-DGGE法和DNA测序分析云南籍G6PD缺乏症患者基因突变类型和特点、方法应用硝基四氮唑蓝（NBT）纸片法进行G6PD缺乏症定性筛查,G6PD／6PGD比值法验证,应用PCR—DGGE法和DNA测序分析46例云南籍G6PD缺乏症患者基因突变类型和特点。结果：46例云南籍G6PD缺乏症样本中有30例经PCR—DGGE法分析G6PDexon12发现有异常电泳条带,DNA测序证实26例（56、52％）为nt-1388G→A,4例（8.7％）nt-1376G→T．而PCR—DGGE法分析G6PDexon2未发现有异常电泳条带的样本出现。结论：（1）nt-1388G→A（56．52％）、nt-1376G→T（8．7％）是云南省主要的基因突变型也是中国人中最常见的两种突变型,揭示中华民族有着共同的起源;（2）所检样本中未发现nt95A→G。（3）应用PCR—DGGE法结合DNA测序检测G6PD缺乏症患者的基因型,阳性检出率高,方法简便、快捷、灵敏、结果准确可靠。     

Modulation of hepatitis B virus secretion by naturally occurring mutations in the S gene

Alteration in hepatitis B virus (HBV) secretion efficiency may have pathological consequences. Naturally occurring mutations that regulate virion secretion have not been defined. We recently identified HBV genomes displaying high (4B), substantially reduced (3.4), or negative (4C) virion secretion. In the present study, the underlying mutations were mapped. A T552C point mutation in the 4B genome was responsible for its enhanced virion secretion, whereas a G510A mutation in 3.4 and G660C in 4C impaired virus secretion. The three point mutations generate M133T, G119E, and R169P substitutions in the S domains of viral envelope proteins, respectively, without modifying the coding capacity of the overlapping polymerase gene. The mutated residues are predicted to lie in the luminal side of the endoplasmic reticulum (ER) or to be embedded in the ER membrane and thus are not involved in contact with core particles during envelopment. Of the two mutations inhibitory of virion secretion, G510A greatly reduced small envelope protein (hepatitis B surface antigen [HBsAg]) levels both inside cells and in culture medium, whereas G660C specifically abolished HBsAg secretion. Surprisingly, a T484G mutation in the 4B genome, generating an I110M substitution in the S domain, could also reduce HBsAg secretion and block virion secretion. However, its inhibitory effect was suppressed in the 4B genome by the T552C mutation, the enhancer of virion secretion. T552C can also override the inhibitory G510A mutation, but not the G660C mutation. These findings suggest a hierarchy in the regulation of virion secretion and a close link between defective virion secretion and impaired HBsAg formation or secretion.     

The Characteristic Changes in Hepatitis B Virus X Region for Hepatocellular Carcinoma: A Comprehensive Analysis Based on Global Data

Objectives

Mutations in hepatitis B virus (HBV) X region (HBx) play important roles in hepatocarcinogenesis while the results remain controversial. We sought to clarify potential hepatocellular carcinoma (HCC)-characteristic mutations in HBx from HBV genotype C-infected patients and the distribution of those mutations in different disease phases and genotypes.

Methods

HBx sequences downloaded from an online global HBV database were screened and then classified into Non-HCC or HCC group by diagnosis information. Patients'' data of patient age, gender, country or area, and viral genotype were also extracted. Logistic regression was performed to evaluate the effects of mutations on HCC risk.

Results

1) Full length HBx sequences (HCC: 161; Non-HCC: 954) originated from 1115 human sera across 29 countries/areas were extracted from the downloaded 5956 HBx sequences. Genotype C occupied 40.6% of Non-HCC (387/954) and 89.4% of HCC (144/161). 2) Sixteen nucleotide positions showed significantly different distributions between genotype C HCC and Non-HCC groups. 3) Logistic regression showed that mutations A1383C (OR: 2.32, 95% CI: 1.34-4.01), R1479C/T (OR: 1.96, 95% CI: 1.05-3.64; OR: 5.15, 95% CI: 2.53-10.48), C1485T (OR: 2.40, 95% CI: 1.41-4.08), C1631T (OR: 4.09, 95% CI: 1.41-11.85), C1653T (OR: 2.58, 95% CI: 1.59-4.19), G1719T (OR: 2.11, 95% CI: 1.19-3.73), and T1800C (OR: 23.59, 95% CI: 2.25-247.65) were independent risk factors for genotype C HBV-related HCC, presenting different trends among individual disease phases. 4) Several genotype C HCC risk mutations pre-existed, even as major types, in early disease phases with other genotypes.

Conclusions

Mutations associated with HCC risk were mainly located in HBx transactivation domain, viral promoter, protein/miRNA binding sites, and the area for immune epitopes. Furthermore, the signatures of these mutations were unique to disease phases leading to HCC, suggesting molecular counteractions between the virus and host during hepatocarcinogenesis.