{"title":"p53 通路基因的遗传变异影响 HBV 相关肝细胞癌患者的存活率","authors":"Liming Qin, Moqin Qiu, Jingmei Tang, Shuyan Liu, Qiuling Lin, Qiongguang Huang, Xiaoxia Wei, Qiuping Wen, Peiqin Chen, Zihan Zhou, Ji Cao, Xiumei Liang, Qian Guo, Cunli Nong, Yizhen Gong, Yuying Wei, Yanji Jiang, Hongping Yu, Yingchun Liu","doi":"10.2147/jhc.s459792","DOIUrl":null,"url":null,"abstract":"<strong>Purpose:</strong> <em>P53</em> is a suppressor gene closely related to carcinogenesis. However, the associations between genetic variants in the p53 signaling pathway and prognosis in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) remain unknown. The current study aims to analyze associations between the single nucleotide polymorphisms (SNPs) in p53 pathway-related genes and survival of patients with HBV-HCC.<br/><strong>Methods:</strong> We evaluated the associations between 4698 SNPs in 70 genes of the p53 pathway and overall survival (OS) of 866 patients in additive genetic models by using Cox proportional hazards regression analysis. Stepwise multivariable Cox regression analysis was conducted to determine the independent effects of identified SNPs in single-locus analyses. The expression of quantitative trait loci (eQTL) was also analyzed using data from GTEx and 1000 Genomes Project, and functional prediction of SNPs was performed by using RegulomeDB v2.2, 3DSNP v2.0, HaploReg v4.2 and VannoPortal.<br/><strong>Results:</strong> We found that two novel SNPs of <em>CD82</em> rs7925603 A > G and <em>PMAIP1</em> rs4396625 A > T, were significantly and independently associated with OS [adjusted hazards ratios (HRs) and 95% confidence intervals (CI) were 1.27 (1.10– 1.48) and 0.77 (0.66– 0.91), respectively; <em>P</em> = 0.001 and = 0.002, respectively] and that the combined risk genotypes of these SNPs showed a significant association with OS in patients with HBV-HCC (<em>P</em><sub>trend</sub> < 0.001). Further eQTL analysis in the GTEx dataset showed that the rs7925603 G allele was associated with lower <em>CD82</em> mRNA expression levels, while the rs4396625 T allele was associated with higher <em>PMAIP1</em> mRNA expression levels in whole blood cells.<br/><strong>Conclusion:</strong> We identified two observed survival-associated SNPs in <em>CD82</em> and <em>PMAIP1</em> in the p53 pathway, which influenced HBV-HCC survival possibly through a mechanism of altering mRNA expression. Large studies are warranted to validate our findings.<br/><br/><strong>Keywords:</strong> hepatocellular carcinoma, hepatitis B virus, p53 signaling pathway, genetic variants, survival<br/>","PeriodicalId":15906,"journal":{"name":"Journal of Hepatocellular Carcinoma","volume":"3 1","pages":""},"PeriodicalIF":4.2000,"publicationDate":"2024-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Genetic Variants in p53 Pathway Genes Affect Survival of Patients with HBV-Related Hepatocellular Carcinoma\",\"authors\":\"Liming Qin, Moqin Qiu, Jingmei Tang, Shuyan Liu, Qiuling Lin, Qiongguang Huang, Xiaoxia Wei, Qiuping Wen, Peiqin Chen, Zihan Zhou, Ji Cao, Xiumei Liang, Qian Guo, Cunli Nong, Yizhen Gong, Yuying Wei, Yanji Jiang, Hongping Yu, Yingchun Liu\",\"doi\":\"10.2147/jhc.s459792\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<strong>Purpose:</strong> <em>P53</em> is a suppressor gene closely related to carcinogenesis. However, the associations between genetic variants in the p53 signaling pathway and prognosis in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) remain unknown. The current study aims to analyze associations between the single nucleotide polymorphisms (SNPs) in p53 pathway-related genes and survival of patients with HBV-HCC.<br/><strong>Methods:</strong> We evaluated the associations between 4698 SNPs in 70 genes of the p53 pathway and overall survival (OS) of 866 patients in additive genetic models by using Cox proportional hazards regression analysis. Stepwise multivariable Cox regression analysis was conducted to determine the independent effects of identified SNPs in single-locus analyses. The expression of quantitative trait loci (eQTL) was also analyzed using data from GTEx and 1000 Genomes Project, and functional prediction of SNPs was performed by using RegulomeDB v2.2, 3DSNP v2.0, HaploReg v4.2 and VannoPortal.<br/><strong>Results:</strong> We found that two novel SNPs of <em>CD82</em> rs7925603 A > G and <em>PMAIP1</em> rs4396625 A > T, were significantly and independently associated with OS [adjusted hazards ratios (HRs) and 95% confidence intervals (CI) were 1.27 (1.10– 1.48) and 0.77 (0.66– 0.91), respectively; <em>P</em> = 0.001 and = 0.002, respectively] and that the combined risk genotypes of these SNPs showed a significant association with OS in patients with HBV-HCC (<em>P</em><sub>trend</sub> < 0.001). Further eQTL analysis in the GTEx dataset showed that the rs7925603 G allele was associated with lower <em>CD82</em> mRNA expression levels, while the rs4396625 T allele was associated with higher <em>PMAIP1</em> mRNA expression levels in whole blood cells.<br/><strong>Conclusion:</strong> We identified two observed survival-associated SNPs in <em>CD82</em> and <em>PMAIP1</em> in the p53 pathway, which influenced HBV-HCC survival possibly through a mechanism of altering mRNA expression. Large studies are warranted to validate our findings.<br/><br/><strong>Keywords:</strong> hepatocellular carcinoma, hepatitis B virus, p53 signaling pathway, genetic variants, survival<br/>\",\"PeriodicalId\":15906,\"journal\":{\"name\":\"Journal of Hepatocellular Carcinoma\",\"volume\":\"3 1\",\"pages\":\"\"},\"PeriodicalIF\":4.2000,\"publicationDate\":\"2024-08-12\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Hepatocellular Carcinoma\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.2147/jhc.s459792\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"ONCOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Hepatocellular Carcinoma","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.2147/jhc.s459792","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"ONCOLOGY","Score":null,"Total":0}
引用次数: 0
摘要
目的：P53 是一种与致癌密切相关的抑制基因。然而，p53 信号通路中的遗传变异与乙型肝炎病毒（HBV）相关肝细胞癌（HCC）预后之间的关系仍不清楚。本研究旨在分析 p53 通路相关基因的单核苷酸多态性（SNPs）与 HBV-HCC 患者生存率之间的关系：我们采用 Cox 比例危险度回归分析法，在加性遗传模型中评估了 p53 通路 70 个基因中 4698 个 SNP 与 866 例患者总生存期（OS）之间的关系。在单病灶分析中，采用逐步多变量 Cox 回归分析确定已识别 SNP 的独立效应。我们还利用GTEx和1000基因组计划的数据分析了定量性状位点（eQTL）的表达，并利用RegulomeDB v2.2、3DSNP v2.0、HaploReg v4.2和VannoPortal对SNPs进行了功能预测：我们发现，CD82 rs7925603 A > G和PMAIP1 rs4396625 A > T这两个新型SNP与OS显著独立相关[调整后危险比（HRs）和95%置信区间（CI）分别为1.27（1.10- 1.48）和 0.77（0.66- 0.91）；P = 0.001 和 = 0.002]，并且这些 SNP 的合并风险基因型与 HBV-HCC 患者的 OS 有显著相关性（Ptrend <0.001）。GTEx 数据集中的进一步 eQTL 分析表明，rs7925603 G 等位基因与较低的 CD82 mRNA 表达水平相关，而 rs4396625 T 等位基因与较高的全血细胞中 PMAIP1 mRNA 表达水平相关：我们在 p53 通路中的 CD82 和 PMAIP1 中发现了两个与生存相关的 SNPs，它们可能通过改变 mRNA 表达的机制影响 HBV-HCC 的生存。关键词：肝细胞癌、乙型肝炎病毒、p53 信号通路、遗传变异、存活率
Genetic Variants in p53 Pathway Genes Affect Survival of Patients with HBV-Related Hepatocellular Carcinoma
Purpose:P53 is a suppressor gene closely related to carcinogenesis. However, the associations between genetic variants in the p53 signaling pathway and prognosis in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) remain unknown. The current study aims to analyze associations between the single nucleotide polymorphisms (SNPs) in p53 pathway-related genes and survival of patients with HBV-HCC. Methods: We evaluated the associations between 4698 SNPs in 70 genes of the p53 pathway and overall survival (OS) of 866 patients in additive genetic models by using Cox proportional hazards regression analysis. Stepwise multivariable Cox regression analysis was conducted to determine the independent effects of identified SNPs in single-locus analyses. The expression of quantitative trait loci (eQTL) was also analyzed using data from GTEx and 1000 Genomes Project, and functional prediction of SNPs was performed by using RegulomeDB v2.2, 3DSNP v2.0, HaploReg v4.2 and VannoPortal. Results: We found that two novel SNPs of CD82 rs7925603 A > G and PMAIP1 rs4396625 A > T, were significantly and independently associated with OS [adjusted hazards ratios (HRs) and 95% confidence intervals (CI) were 1.27 (1.10– 1.48) and 0.77 (0.66– 0.91), respectively; P = 0.001 and = 0.002, respectively] and that the combined risk genotypes of these SNPs showed a significant association with OS in patients with HBV-HCC (Ptrend < 0.001). Further eQTL analysis in the GTEx dataset showed that the rs7925603 G allele was associated with lower CD82 mRNA expression levels, while the rs4396625 T allele was associated with higher PMAIP1 mRNA expression levels in whole blood cells. Conclusion: We identified two observed survival-associated SNPs in CD82 and PMAIP1 in the p53 pathway, which influenced HBV-HCC survival possibly through a mechanism of altering mRNA expression. Large studies are warranted to validate our findings.
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