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Abstract：
BACKGROUND: Hypoxia is often involved in tumor microenvironment, and the hypoxia-induced signaling pathways play a key role in aggressive cancer phenotypes, including angiogenesis, immune evasion, and therapy resistance. However, it is unknown what role genetic variants in the hypoxia-related genes play in survival of patients with non-small cell lung cancer (NSCLC).
METHODS: We evaluated the associations between 16,092 single-nucleotide polymorphisms (SNPs) in 182 hypoxia-related genes and survival outcomes of NSCLC patients. Data from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial were used as the discovery dataset, and the Harvard Lung Cancer Susceptibility (HLCS) Study served as the replication dataset. We also performed additional linkage disequilibrium analysis and a stepwise multivariable Cox proportional hazards regression analysis in the PLCO dataset.
RESULTS: An independent SNP, ERRFI1 rs28624 A > C, was identified with an adjusted hazards ratio (HR) of 1.31 (95% CI = 1.14-1.51, p = 0.0001) for overall survival (OS). In further analyses, unfavorable genotypes AC and CC, compared with the AA genotype, were associated a worse OS (HR = 1.20, 95% CI = 1.03-1.39, p = 0.014) and disease-specific survival (HR = 1.21, 95% CI = 1.04-1.42, p = 0.016). Further expression quantitative trait loci analysis indicated that ERRFI1 rs28624C genotypes were significantly associated with higher ERRFI1 mRNA expression levels in the whole blood. Additional analysis showed that high ERRFI1 mRNA expression levels were associated with a worse OS in patients with lung adenocarcinoma.
CONCLUSIONS: Our findings suggest that genetic variants in the hypoxia-related gene ERRFI1 may modulate NSCLC survival, potentially through their effect on the gene expression.
METHODS: We evaluated the associations between 16,092 single-nucleotide polymorphisms (SNPs) in 182 hypoxia-related genes and survival outcomes of NSCLC patients. Data from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial were used as the discovery dataset, and the Harvard Lung Cancer Susceptibility (HLCS) Study served as the replication dataset. We also performed additional linkage disequilibrium analysis and a stepwise multivariable Cox proportional hazards regression analysis in the PLCO dataset.
RESULTS: An independent SNP, ERRFI1 rs28624 A > C, was identified with an adjusted hazards ratio (HR) of 1.31 (95% CI = 1.14-1.51, p = 0.0001) for overall survival (OS). In further analyses, unfavorable genotypes AC and CC, compared with the AA genotype, were associated a worse OS (HR = 1.20, 95% CI = 1.03-1.39, p = 0.014) and disease-specific survival (HR = 1.21, 95% CI = 1.04-1.42, p = 0.016). Further expression quantitative trait loci analysis indicated that ERRFI1 rs28624C genotypes were significantly associated with higher ERRFI1 mRNA expression levels in the whole blood. Additional analysis showed that high ERRFI1 mRNA expression levels were associated with a worse OS in patients with lung adenocarcinoma.
CONCLUSIONS: Our findings suggest that genetic variants in the hypoxia-related gene ERRFI1 may modulate NSCLC survival, potentially through their effect on the gene expression.
摘要：
背景：缺氧通常与肿瘤微环境有关，缺氧诱导的信号通路在侵袭性癌症表型中起关键作用，包括血管生成,免疫逃避,和治疗抵抗。然而,缺氧相关基因中的遗传变异在非小细胞肺癌(NSCLC)患者生存中的作用尚不清楚.
方法：我们评估了182个缺氧相关基因中16,092个单核苷酸多态性（SNPs）与NSCLC患者生存结局之间的关联。来自前列腺的数据，肺，结肠直肠,和卵巢癌（PLCO）筛查试验被用作发现数据集，和哈佛肺癌易感性（HLCS）研究作为复制数据集。我们还在PLCO数据集中进行了额外的连锁不平衡分析和逐步多变量Cox比例风险回归分析。
结果：一个独立的SNP，ERRFI1rs28624A>C,总生存期（OS）的校正风险比（HR）为1.31（95％CI=1.14-1.51，p=0.0001）。在进一步的分析中，不利基因型AC和CC，与AA基因型相比，与不良OS(HR=1.20,95%CI=1.03-1.39,p=0.014)和疾病特异性生存率(HR=1.21,95%CI=1.04-1.42,p=0.016)相关.进一步的表达数量性状基因座分析表明，ERRFI1rs28624C基因型与全血中较高的ERRFI1mRNA表达水平显着相关。其他分析表明，高ERRFI1mRNA表达水平与肺腺癌患者的OS恶化有关。
结论：我们的研究结果表明，缺氧相关基因ERRFI1的遗传变异可能调节NSCLC的生存，可能通过它们对基因表达的影响。
方法：我们评估了182个缺氧相关基因中16,092个单核苷酸多态性（SNPs）与NSCLC患者生存结局之间的关联。来自前列腺的数据，肺，结肠直肠,和卵巢癌（PLCO）筛查试验被用作发现数据集，和哈佛肺癌易感性（HLCS）研究作为复制数据集。我们还在PLCO数据集中进行了额外的连锁不平衡分析和逐步多变量Cox比例风险回归分析。
结果：一个独立的SNP，ERRFI1rs28624A>C,总生存期（OS）的校正风险比（HR）为1.31（95％CI=1.14-1.51，p=0.0001）。在进一步的分析中，不利基因型AC和CC，与AA基因型相比，与不良OS(HR=1.20,95%CI=1.03-1.39,p=0.014)和疾病特异性生存率(HR=1.21,95%CI=1.04-1.42,p=0.016)相关.进一步的表达数量性状基因座分析表明，ERRFI1rs28624C基因型与全血中较高的ERRFI1mRNA表达水平显着相关。其他分析表明，高ERRFI1mRNA表达水平与肺腺癌患者的OS恶化有关。
结论：我们的研究结果表明，缺氧相关基因ERRFI1的遗传变异可能调节NSCLC的生存，可能通过它们对基因表达的影响。
