HBsAg HBs HBV S. [DOI] /j.issn , China

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1 Med J Chin PLA, Vol. 41, No. 11, November 1, HBsAg HBs HBV S N- [ ] HBsAg HBs( ) HBVS (MHR) N- (HCC) HBVPCR HBV S MHR HCC 18 HCCHCC SN- >40 HBsAg > HBeAgMRH N- HBV HCC (OR= %CI 1.843~9.941 P=0.001 OR= %CI 1.633~6.060 P=0.001 OR= %CI 1.010~4.357 P=0.047 OR= %CI 1.842~ P=0.001) (ALT) HBs> HBeHBV DNAHCC 18 HCC8 HCC 1~4 N- HBV S MHR N-HCC HBsAg HBs MHRHBV HCC [] N- [ ] R735.7 [ ] A [ ] (2016) [DOI] /j.issn hepatitis B virus in HBsAg and anti-hbs coexistent patients QIAO Yan 1,2, XU Zhi-hui 2, LU Shan-shan 2, LI Xiao-dong 2, HUANG Peng-yu 2, LIU Yan 2, ZHAO Li 2, YANG Yue 2, XU Dongping 2*, LI Jin 3* 1 Clinical Medicine College, Guilin Medical University, Guilin, Guangxi , China 2 Research Center for Clinical and Translational Medicine, 3 Department of Medical Administration, 302 Hospital of PLA, Beijing , China * Corresponding author. XU Dong-ping, xudongping302@sina.com; LI Jin, lijin302@hotmail.com This work was supported by the National Natural Science Foundation of China ( , ) and Capital Health Development Research Special Independent Innovation Project ( ) [Abstract] Objective To investigate the association of additional N-glycosylation mutation in major hydrophilic region (MHR) of hepatitis B virus (HBV) S gene with the risk of hepatocellular carcinoma (HCC) in HBsAg and anti-hbs coexistent patients. Methods A total of 284 patients with coexistence of HBsAg and anti-hbs were enrolled in this study, who were admitted in 302 Hospital of PLA from July 2009 to June HBV DNA was extracted from serum samples and subjected to nested PCR for full-length S-gene sequencing. The association of MHR additional N-glycosylation mutation and clinical parameters with HCC occurrence risk was analyzed. Specifically, the additional N-glycosylation mutation was dynamically analyzed pre- and post-hcc occurrence for 18 patients. Results Multivariate analysis showed that age >40 years, HBsAg >median, HBeAg negativity, and additional N-glycosylation mutation in MHR were associated with HCC occurrence for the HBsAg and anti-hbs coexistent patients (OR=4.281, 95%CI , P=0.001; OR=3.146, 95%CI , P=0.001; OR=2.097, 95%CI , P=0.047; and OR=4.381, 95%CI , P=0.001). In contrast, ALT, anti-hbs, anti-hbe, and HBV DNA levels had no significant association with HCC occurrence. Dynamical analysis showed [ ]( ) ( ) [ ] [ ] ( ) ( ) ( ) [ ] xudongping302@sina.com lijin302@hotmail.com

2 that the additional N-glycosylation mutation had already developed 1-4 years prior to HCC occurrence in the 8 of 18 observed patients. Conclusion Additional N-glycosylation mutation in MHR of HBV S gene had close association with HCC occurrence in HBsAg and anti-hbs coexistent patients, suggesting that HBsAg and anti-hbs coexistence and additional N-glycosylation mutation together could serve as a predictive indicator for HCC occurrence in chronic HBV-infected patients. [Key words] hepatitis B, chronic; carcinoma, hepatocellular; mutation; N-glycosylation (hepatocellular carcinoma HCC) 3 [1] [2-3] 60% (hepatitis B virus HBV) HBV HCC HBV DNAC CS/S HCC [4-8] HBsAg HBs HCC [9] HBV S (MHR) HBs [10] HBV S MHR N- HBV [11] N- s NCT N- N-X-T/S (X P ) HBsAg HBsHCC HCCHBV S MHR N HBV 72 HCC (HCC ) 212 HCC ( HCC ) 18 HCC 1~4( 2.5) [12-13] HIV 1.2 DNA ( ) PCR ( )PCR (ABI ) ( Roche ) ELISA ( ) Olympus AU5400 Light Cycler 480HBV DNA HBV DNA S PCR DNA Out HBV DNA PCRHBV S PSup3 5'-TC GCAGAAGATCTCAATCTCG-3'( ) SB1R 5'-AGGTGAAGCGAAGTGCACAC-3' ( ) PSup4 5'-CATAAGGTGGGAAACTTTAC-3'( ) SB2R 5'-TTCCGCAGTATGGATCGGC AG-3'( ) 25 l 2 Mix Buffer(1/10 )12.5 l PSup3(1/10 )0.25 l SB1R 0.25 l HBV DNA 10 l H 2 O2 l94 5min 94 40s 57 1min12s 72 2min24s min 50 l2 Mix Buffer 25 l PSup4 0.5 l SB2R 0.5 l4 l H 2 O50 l94 5min 94 40s 57 1min 72 2min min PCR DNA S NCBI genotyping tool( projects/genotyping/formpagex.cgi)hbv/c S ( AB014381)S 1.4SPSS 18.0 ( ) x±s t logistic(or) OR 95% (CI) P< HBV S 284N- 11.3%(32/284)HCC 15 sq129n NGT sg130n+t131n NNS st131n+m133t NST KNA insertion NAS st116n NST s NTSTT insertion NTS st131n+m133t 131-

3 Med J Chin PLA, Vol. 41, No. 11, November 1, NST sg130n NTS st113n STT deletion NST & st131n+ M133T NST NST53.3%(8/15) HCC 17 sg130n NTS st131n+m133t NST st116n NST &st131n+ M133T NST st113n NST TTN insertion NST NST 70.6%(12/17) 2.2 HCCHCC HBV S MHR HCCHCC HCCHBsAg HCC (P<0.01 P<0.05) HBV DNA (ALT) HCC (P<0.01) N- (20.8%) HCC (8.0% P <0.01)HBs (TBIL) (P>0.05 1) Tab.1 The clinical features of the 284 patients with HBsAg and HBsAb double positivity Item HCC (n=72) Non-HCC (n=212) P value Male [n(%)] 51(85.0) 107(83.6) Age(year) 52.4± ± HBsAg (COI) 4765± ± Anti-HBs (U/L) 54.2( ) 43.7( ) TBIL( mol/l) 18.6( ) 16.8( ) ALT(U/L) 39.0(26-39) 61(29-60) HBV DNA(log 10 U/ml) 4.77± ± Additional N-glycosylation mutation [n(%)] 15(20.8) 17(8.0) TBIL. Total bilirubin; ALT. Alanine aminotransferase HCCHCC HCCHBV DNA ALT HCC (P<0.05) N- HCC (21.7% vs 9.4% P<0.05) HBsAg HBs TBIL (P>0.05 2) Item 2 HCCHCC Tab.2 The clinical features of patients after just age HCC (n=60) Non-HCC (n=128) P value Male [n(%)] 51(85.0) 107(83.6) Age (year) 49.87± ± HBsAg (COI) 5207( ) 4380( ) Anti-HBs (U/L) 51.6( ) 43.2( ) TBIL ( mol/l) 19.2( ) 16.8( ) ALT (U/L) 36.88± ± HBV DNA (log 10 U/L) 4.69± ± Additional N-glycosylation mutation [n(%)] 13(21.7) 12(9.4) HBV HCC HCC >40 HBsAg> HBeAg N- HCC (P<0.01) ALT>40U/L HBV DNA HBs> HBe ( 3) Logistic HCC logistic >40 HBsAg> HBeAg N- HCC (P<0.05) >40 HCC HBsAg> HCC 3.146N- N Tab.3 Univariate analyses of risk factors for predicting HCC development Item HCC (n=72) Non-HCC(n=212) OR (95% CI) P value Male [n(%)] 58(80.6) 174(82.0) 0.095( ) Age>40 years [n(%)] 64(88.9) 128(60.4) 5.677( ) HBsAg>median 49(68.1) 94(44.3) 2.583( ) Anti-HBs>median 40(55.6) 103(48.6) 1.585( ) ALT >40U/L [n(%)] 36(47.4) 132(62.3) 0.606( ) HBV DNA (log 10 U/ml) level [n(%)] 1( ) 23(31.8) 49(23.1) 1.561( ) ( ) 22(30.6) 68(32.0) 0.932( ) ( 6) 19(26.4) 76(35.8) 0.642( ) HBeAg-negative [n(%)] 31(43.1) 48(22.6) 2.583( ) Anti-HBe-positive [n(%)] 39(54.2) 87(41.0) 1.698( ) Additional N-glycosylation mutation [n(%)] 15(19.7) 17(8.0) 3.019( ) HBsAg median: 4532 COI; Anti-HBs median: 48U/L

4 HBeAg HBeAg ( 4) 2.3 HCC N- 4 logistic Tab.4 Results of logistic regression analysis Item OR 95% CI P value Male Age >40 years HBsAg > median Anti-HBs > median ALT >40U/L HBV DNA (log 10 U/ml) level [n(%)] 1( ) ( ) ( 6) HBeAg negative Anti-HBe positive Additional N-glycosylation mutation [n(%)] HBsAg median: 4532 COI; Anti-HBs median: 48U/L Years before diagnosis of HCC P1 P2 P3 P4 P5 P6 P7 P HCC HBV18 HCC ( 2) 8 HCC 1~4 1 N S MHR N- 8 4(P2 P3 P5 P6) HCC MHR N- HCC 3(P1 P7 P8) HCCMHR N- HCCN- HBs P4 HCC MHR N- HCCN- HBs P2HBsAg HBsAg HBs HBsAg HBs MHR N- HCC ( 1) Diagnosis of HCC Year after diagnosis of HCC 1 Age/Gender N-glycosylation mutation 82/M GTS NTS 48/M insertion NGT 70/M TSM NST 59/M QGT NGT 57/M insertion NTS 61/M TSM NST 56/M TST NST 60/M TST NST, TSM NST 1N- HBsAg HBs HCC Fig.1 Dynamical observation of additional N-glycosylation mutation in 8 HCC patients with coexistence of HBsAg and anti-hbs GTS NTS, insertion NGT, TSM NST, QGT NGT, insertion NTS, TST NST;. HBsAg positive,. Anti-HBs positive 3 HBV S(S )S [14] HBsAg 3 N ( 1~98) MHR( 99~169) C( 170~226) MHR ( 124~147) S SMHR N- (N-X-T/S X P) MHR s146~148 N- N- N- [15-16] HBsAg HBs HBV 5% [17] Jang [18] 755HBVHBsAg HBs HCC HBsAg [22.9%(11/48) vs 7.9%(56/707) P=0.002] Seo [9] 1042HBV HCC (12.7% 23.4% 69.4% vs 4.9% 13% 20.6%) HBV S MHR N- (11.3% vs 2.9% P<0.01) HCC N- 46.9% 22.6% (P<0.01) [19] HBsAg HBs HCC

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