Division of Genome Biology, National Cancer Center Research Institute, 5-1-1, Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, 3-25-8, Nishi-Shimbashi, Minato-ku, Tokyo, 105-8461, Japan.
Sci Rep. 2023 Aug 9;13(1):12944. doi: 10.1038/s41598-023-40000-3.
Liver cancer, particularly hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), is more common in Asians than in Caucasians. This is due, at least in part, to regional differences in the prevalence of exogenous factors such as HBV; however, endogenous factors specific to Asia might also play a role. Such endogenous factors include HLA (human leukocyte antigen) genes, which are considered candidates due to their high racial diversity. Here, we performed a pancancer association analysis of 147 alleles of HLA-class I/II genes (HLA-A, B, and C/DRB1, DQA1, DQB1, DPA1, and DPB1) in 31,727 cases of 12 cancer types, including 1684 liver cancer cases and 107,103 controls. HLA alleles comprising a haplotype prevalent in Asia were significantly associated with pancancer risk (e.g., odds ratio [OR] for a DRB115:02 allele = 1.12, P = 2.7 × 10), and the associations were particularly strong in HBV-related HCC (OR 1.95, P = 2.8 × 10). In silico prediction suggested that the DRB115:02 molecule encoded by the haplotype does not bind efficiently to HBV-derived peptides. RNA sequencing indicated that HBV-related HCC in carriers of the haplotype shows low infiltration by NK cells. These results indicate that the Asian-prevalent HLA haplotype increases the risk of HBV-related liver cancer risk by attenuating immune activity against HBV infection, and by reducing NK cell infiltration into the tumor.
肝癌，尤其是乙型肝炎病毒（HBV）相关的肝细胞癌（HCC），在亚洲人中比在白种人中更为常见。这至少部分归因于 HBV 等外源因素在地域上的差异；然而，亚洲特有的内在因素也可能起作用。这些内在因素包括 HLA（人类白细胞抗原）基因，由于其种族多样性高，被认为是候选基因。在这里，我们对 31727 例 12 种癌症类型（包括 1684 例肝癌和 107103 例对照）的 147 个 HLA Ⅰ/Ⅱ类基因（HLA-A、B 和 C/DRB1、DQA1、DQB1、DPA1 和 DPB1）的 147 个等位基因进行了泛癌症关联分析。在亚洲流行的单倍型组成的 HLA 等位基因与泛癌症风险显著相关（例如，DRB115:02 等位基因的比值比 [OR]为 1.12，P=2.7×10），并且在 HBV 相关 HCC 中关联特别强（OR 1.95，P=2.8×10）。计算机预测表明，该单倍型编码的 DRB115:02 分子不能有效地与 HBV 衍生肽结合。RNA 测序表明，携带该单倍型的 HBV 相关 HCC 中 NK 细胞浸润程度较低。这些结果表明，亚洲流行的 HLA 单倍型通过削弱针对 HBV 感染的免疫活性以及减少 NK 细胞浸润肿瘤，增加了 HBV 相关肝癌的风险。
