Prognostic value of Notch receptors in postsurgical patients with hepatitis B virus-related hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most prevalent malignancies and a major cause of cancer involved death worldwide. Prognosis remains poor because of high recurrence rates and lack of effective relapse prevention strategies. Notch pathway plays an important role in tumor progression and metastasis, and it is associated with the prognosis of cancer. A total of 465 hepatitis B virus (HBV)-related HCC patients who underwent surgery were enrolled. Single nucleotide polymorphisms (SNP) of Notch pathway receptors were genotyped using Sanger DNA sequencing. Kaplan-Meier curves and the Cox proportional hazards regression model were adopted to analyze the association of polymorphisms and mRNA expression with clinical and pathological features, respectively. Four SNPs (rs1043996 in Notch3 and rs422951, rs520692, rs3830041 in Notch4) were significantly associated with overall survival (OS) (P = 0.023, P = 0.042, P = 0.028, and P = 0.001 respectively). Patients carrying the AA genotype in rs1043996 and TT/TC genotypes in rs422951 and rs520692 significantly decreased risks of death, compared to those carrying the AG/GG genotype in rs1043996 and CC genotype in rs422951 and rs520692, respectively. Patients carrying the TT genotype in rs3830041 showed poorer OS, compared with those carrying the TC/CC genotype. A haplotype block (rs422951 was in strong LD with rs520692, r2  = 0.843) was identified in Notch4. Notch3 mRNA expression significantly increased in tumor tissue, compared with nontumor normal tissue (P < 0.0001). Moreover, higher expression of Notch3 was associated with poorer OS (HR = 2.11, 95% CI = 1.32-3.37, P = 0.002) and shorter recurrence time of HBV-related HCC (HR = 1.96, 95% CI = 1.31-2.93, P = 0.001). Our findings collectively indicate that Notch receptors variants (rs1043996 in Notch3 and rs422951, rs520692, rs3830041 in Notch4) are independent predictive targets for OS in HBV-related HCC patients. Notch3 expression is a potential prognostic biomarker of OS and recurrence-free survival (RFS) prediction in HBV-related HCC patients following surgical treatment.

Yu T ，Han C ，Zhu G ，Liao X ，Qin W ，Yang C ，Liu Z ，Su H ，Liu X ，Yu L ，Liu Z ，Lu S ，Chen Z ，Liang Y ，Huang J ，Qin X ，Gui Y ，Li J ，Peng T ... -  《Cancer Medicine》

Genetic polymorphisms in the Wnt/β-catenin pathway genes as predictors of tumor development and survival in patients with hepatitis B virus-associated hepatocellular carcinoma.

Wnt/β-catenin signaling has a pivotal role in the pathogenesis of hepatocellular carcinoma (HCC). The present study aimed to determine whether genetic variation in the Wnt/β-catenin signaling pathway is associated with the development and/or progression of HCC and the survival of patients with hepatitis B virus (HBV)-associated HCC. We assessed seven single nucleotide polymorphisms (SNPs) of the AXIN1, AXIN2, CTNNB1, and WNT2 genes in 245 patients with HBV-associated HCC and 483 chronic HBV carriers without HCC. We analyzed the association of each SNP with HCC development or progression and overall survival. The CTNNB1 rs3864004 A allele was associated with a decreased risk of HCC development (P=0.049). Haplotype analysis revealed a significantly higher frequency of CTNNB1 G-A/G-A haplotype at rs3864004 and rs4135385 positions in patients with HCC than in chronic HBV carriers without HCC (P=0.042). The AXIN1 rs1805105 T>C SNP was associated with small tumor size and early tumor stage and the WNT2 rs39315 G allele was associated with advanced tumor stage in HCC. In Kaplan-Meier analysis, carriers of the AXIN1 rs214252 C allele showed longer survival than those with the TT genotype (P=0.020). In multivariate Cox regression analysis, absence of CTNNB1 haplotype A-A at rs3864004 and rs4135385 positions and advanced tumor stage were independent poor predictors of patient survival in patients with HCC. These findings suggest that the genetic polymorphisms in CTNNB1 gene might affect tumor development and survival in patients with HBV-associated HCC.

Kim SS ，Cho HJ ，Lee HY ，Park JH ，Noh CK ，Shin SJ ，Lee KM ，Yoo BM ，Lee KJ ，Cho SW ，Cheong JY ... -  《-》

Notch1 and Notch4 are markers for poor prognosis of hepatocellular carcinoma.

Ahn S ，Hyeon J ，Park CK 《-》

Positive HBcAb is associated with higher risk of early recurrence and poorer survival after curative resection of HBV-related HCC.

Previous studies predicted the prognosis of hepatocellular carcinoma (HCC) mainly based on tumour-related factors, whereas the impacts of hepatitis B virus (HBV)-related factors are usually ignored. The objective of this exploratory study was to investigate the prognostic role of hepatitis B core antibody (HBcAb) on post-operative survival and recurrence of HCC. A retrospective analysis of 3388 HBsAg positive (HBV-related) HCC patients treated by curative resection was performed. Multivariate analysis of independent prognostic factors was performed by Cox proportional hazards regression model. HBcAb positivity was an independent prognostic factor for recurrence-free survival (RFS) of HBV-related patients (P < 0.001, HR: 1.723, 95% CI: 1.278-2.324), and the 1-, 3-, 5-year RFS rates for HBcAb-negative patients were significantly better than those of HBcAb-positive patients (92.5%, 72.1% and 65.9% vs 77.9%, 58.6% and 46.9%, P < 0.001). HBcAb-positive HCC was much bigger (P = 0.006), more often involved with vascular invasion (P = 0.001), elevated AFP (P = 0.001) and ALT (P = 0.046) levels, but less often involved with capsule formation (P = 0.034). Besides vascular invasion, tumour size, interferon-α treatment, AFP and GGT level, HBcAb positivity was an independent prognostic factor for early intrahepatic recurrence of HBV-related patients (P = 0.025, HR: 1.766, 95% CI: 1.073-2.907) and the majority of HBcAb-positive recurrence were early recurrence while most of HBcAb-negative recurrence were late recurrence (P = 0.004). Positive HBcAb may represent a more invasive phenotype of HBV-related HCC, and is associated with a higher risk of early intrahepatic recurrence and poorer RFS of HBV-related patients after curative resection.

Li T ，Wang SK ，Zhou J ，Sun HC ，Qiu SJ ，Ye QH ，Wang L ，Fan J ... -  《-》

Genetic polymorphism of interleukin-16 influences susceptibility to HBV-related hepatocellular carcinoma in a Chinese population.

Interleukin-16 (IL16) as a multifunctional cytokine, plays a key role in inflammatory and autoimmune diseases as well as tumour growth and progression. Recently, genetic polymorphisms of IL16 have been reported to be associated with susceptibility to a range of cancers. This study was undertaken to investigate the IL16 gene polymorphisms and determine whether these genetic factors are related to the occurrence of hepatocellular carcinoma (HCC) in a Chinese population. We analyzed three polymorphisms of the IL16 gene (rs11556218T/G, rs4072111C/T and rs4778889T/C) in 206 patients with HBV-related HCC, 270 chronic hepatitis B patients and 264 healthy controls, using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method and DNA sequencing technology. IL16 polymorphisms were not associated with risk of HCC when compared with healthy controls. However, IL16 polymorphisms were significantly associated with susceptibility to HBV-related HCC when using chronic hepatitis B patients as controls. The rs11556218T/G TG and GG genotypes were associated with significantly increased risk of HBV-related HCC compared with the TT genotype (OR = 1.96 and OR = 3.33). The data also revealed that subjects with the G allele appeared to have higher susceptibility to HBV-related HCC than those with the T allele (OR = 2.10). Under the dominant model genotype TG+GG appeared to be associated with an increased risk of HBV-related HCC (OR = 2.18). The rs4072111C/T TT genotype was associated with a significantly increased risk of HBV-related HCC compared with the CC genotype (OR = 6.67). Polymorphisms of the IL16 gene were significantly associated with susceptibility to chronic hepatitis B when using healthy subjects as controls. The rs11556218T/G TG and GG genotypes were associated with significantly decreased risk of chronic hepatitis B compared with the TT genotype (OR = 0.49 and OR = 0.29). The data also revealed that subjects with the G allele appeared to have lower susceptibility to chronic hepatitis B than those with the T allele (OR = 0.46). Under the dominant model genotype TG + GG appeared to have lower susceptibility to chronic hepatitis B (OR = 0.44). This study showed that the genotypes and allele of IL16 SNPs were associated with chronic HBV infection and HCC. However, further investigation with a larger sample size and haplotype analysis with other SNPs may be required to validate the genetic effects of the IL16 polymorphisms on chronic HBV infection and HCC.

Li S ，Deng Y ，Chen ZP ，Huang S ，Liao XC ，Lin LW ，Li H ，Peng T ，Qin X ，Zhao JM ... -  《-》