Department of Internal Medicine, University of Ulsan College of Medicine, Ulsan University Hospital, Ulsan, Korea.
Hepatology. 2014 May;59(5):1912-20. doi: 10.1002/hep.26655. Epub 2014 Mar 27.
Our goal was to determine whether single-nucleotide polymorphisms (SNPs) of telomere maintenance genes influence the development and clinical outcomes of patients with hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC). We evaluated 20 SNPs of five telomere maintenance genes in 702 patients with HCC and 351 hepatitis B virus surface antigen-positive controls without HCC. Significant SNPs were then validated in an independent cohort of 857 HCC patients and 429 controls. We assessed the association of each SNP with the development of HCC and overall survival through a multivariate Cox proportional analysis. A significantly increased risk of HCC development was identified for the telomerase-associated protein 1 (TEP1) rs1713449 SNP in both the discovery and replication phases (combined odds ratio = 1.42, P = 9.378 × 10(-5) ). In addition, the TEP1 rs1713449, TEP1 rs872072, protection of telomeres 1 homolog rs7784168, telomerase reverse transcriptase rs13167280, and telomeric repeat binding factor 1 rs2306494 SNPs had a significant effect on the overall survival, and a similar survival effect was validated in the replication cohort. Moreover, there was a significant dose-dependent association between the number of putatively high-risk genotypes of the five aforementioned SNPs and overall survival. The median survival time was significantly prolonged for patients with HCC with two or fewer putatively high-risk genotypes versus those with three or more high-risk genotypes (85 versus 44 months, log-rank P = 4.483 × 10(-5) ), and this was demonstrated in the replication cohort (52 versus 37 months, log-rank P = 0.026).
These observations suggest that the SNPs of telomere maintenance genes play a potential role in the development of HCC and the survival of HCC patients with chronic HBV infections.
研究端粒维持基因的单核苷酸多态性（SNP）是否影响乙型肝炎病毒（HBV）相关肝细胞癌（HCC）患者的发生和临床结局。
我们在 702 例 HCC 患者和 351 例乙型肝炎病毒表面抗原阳性且无 HCC 的对照者中评估了 5 个端粒维持基因的 20 个 SNP。随后在独立的 857 例 HCC 患者和 429 例对照者队列中对显著 SNP 进行了验证。通过多变量 Cox 比例分析评估了每个 SNP 与 HCC 发生和总生存的相关性。
在发现和验证阶段，端粒酶相关蛋白 1（TEP1）rs1713449 SNP 均与 HCC 发生风险显著增加相关（联合优势比=1.42，P=9.378×10(-5)）。此外，TEP1 rs1713449、TEP1 rs872072、端粒保护因子 1 同源物 rs7784168、端粒酶逆转录酶 rs13167280 和端粒重复结合因子 1 rs2306494 SNP 对总生存也有显著影响，在验证队列中也验证了相似的生存效果。此外，上述 5 个 SNP 的假定高危基因型数量与总生存之间存在显著的剂量依赖性关联。与具有 3 个或更多高危基因型的患者相比，具有 2 个或更少假定高危基因型的 HCC 患者的中位生存时间显著延长（85 个月比 44 个月，log-rank P=4.483×10(-5)），在验证队列中也有类似的结果（52 个月比 37 个月，log-rank P=0.026）。
这些观察结果表明，端粒维持基因的 SNP 可能在慢性 HBV 感染患者 HCC 的发生和生存中发挥作用。
