HLA-DQB1 多态性可预测接受肝切除术的乙型肝炎病毒相关肝细胞癌患者的生存情况。

Polymorphisms of HLA-DQB1 predict survival of hepatitis B virus-related hepatocellular carcinoma patients receiving hepatic resection.

机构信息

Department of Hepatobiliary Surgery, First Affiliated Hospital of Guangxi Medical University, Nanning, 530021 Guangxi Province, China.

出版信息

Clin Res Hepatol Gastroenterol. 2016 Dec;40(6):739-747. doi: 10.1016/j.clinre.2016.04.005. Epub 2016 Jun 7.

DOI:10.1016/j.clinre.2016.04.005

PMID:27288300

Abstract

OBJECTIVE

Human leukocyte antigen (HLA)-DQB1 genetic polymorphisms are associated with an increased risk of hepatitis B virus-related hepatocellular carcinoma (HBV-related HCC). We aimed to evaluate the influence of genetic polymorphisms in HLA-DQB1 exon region and neighboring single nucleotide polymorphisms (SNPs rs9275572 and rs2244546) on survival of HBV-related HCC patients undergoing hepatic resection.

METHODOLOGY

All SNPs were genotyped by sequencing DNA isolated from tumor samples of 483 patients with HBV-related HCC.

RESULTS

We identified rs9275572 and HLA-DQB1 haplotype CCCCC (constituted by rs1130375C, rs12722107C, rs12722106C, rs36222416C and rs3189152C) were significantly associated with overall survival (OS) of HBV-related HCC patients (P=0.015 and 0.049, respectively), after adjusting for serum AFP level, the Barcelona Clinic Liver Cancer (BCLC) stages, Child-Pugh score, regional invasion, radical hepatic resection and adjuvant antiviral treatment. In stratified analyses, the AG/GG genotype of rs9275572 significantly decreased risk of death among patients with younger age, serum AFP levels ≥400ng/mL, tumor size ≥10cm, BCLC stage A and radical hepatic resection. HLA-DQB1 haplotype CCCCC was significantly protective for male patients, patients with serum AFP levels <400ng/mL, tumor size ≥10cm, BCLC stage B/C, postoperative adjuvant TACE/TAC/TAE, radical hepatic resection and patients with adjuvant antiviral treatment. Moreover, gene-dosage effects were also observed, patients with SNP rs9275572 AG/GG genotypes and Block2 CCCCC haplotype had a decreased risk of death compared to others after adjusting for serum AFP level, BCLC stages, Child-Pugh score, regional invasion, radical hepatic resection and adjuvant antiviral treatment (adjusted HR=0.38, 95% CI=0.20-0.73, P=0.004).

CONCLUSIONS

The AG/GG genotype of rs9275572 and HLA-DQB1 Block2 CCCCC haplotype may have protective effects in HBV-related HCC patients receiving hepatic resection.

摘要

目的

人类白细胞抗原（HLA）-DQB1 基因多态性与乙型肝炎病毒相关肝细胞癌（HBV 相关 HCC）的风险增加有关。本研究旨在评估 HLA-DQB1 外显子区域和相邻单核苷酸多态性（SNP rs9275572 和 rs2244546）的遗传多态性对接受肝切除术的 HBV 相关 HCC 患者生存的影响。

方法

所有 SNP 均通过对 483 例 HBV 相关 HCC 患者肿瘤样本中分离的 DNA 进行测序进行基因分型。

结果

我们发现 rs9275572 和 HLA-DQB1 单倍型 CCCCC（由 rs1130375C、rs12722107C、rs12722106C、rs36222416C 和 rs3189152C 组成）与 HBV 相关 HCC 患者的总生存（OS）显著相关（P=0.015 和 0.049），在调整了血清 AFP 水平、巴塞罗那临床肝癌（BCLC）分期、Child-Pugh 评分、区域侵袭、根治性肝切除和辅助抗病毒治疗后。在分层分析中，rs9275572 的 AG/GG 基因型显著降低了年龄较小、血清 AFP 水平≥400ng/mL、肿瘤大小≥10cm、BCLC 分期 A 和根治性肝切除的患者的死亡风险。HLA-DQB1 单倍型 CCCCC 对男性患者、血清 AFP 水平<400ng/mL、肿瘤大小≥10cm、BCLC 分期 B/C、术后辅助 TACE/TAC/TAE、根治性肝切除和辅助抗病毒治疗的患者具有显著的保护作用。此外，还观察到基因剂量效应，与其他患者相比，SNP rs9275572 的 AG/GG 基因型和 Block2 CCCCC 单倍型的患者在调整了血清 AFP 水平、BCLC 分期、Child-Pugh 评分、区域侵袭、根治性肝切除和辅助抗病毒治疗后，死亡风险降低（调整 HR=0.38，95%CI=0.20-0.73，P=0.004）。