Department of Respiratory Oncology, Guangxi Cancer Hospital, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, China.
Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina, USA.
Cancer Med. 2024 Aug;13(15):e70073. doi: 10.1002/cam4.70073.
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).
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.
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.
Our findings suggest that genetic variants in the hypoxia-related gene ERRFI1 may modulate NSCLC survival, potentially through their effect on the gene expression.
缺氧通常与肿瘤微环境有关，缺氧诱导的信号通路在包括血管生成、免疫逃逸和治疗耐药在内的侵袭性癌症表型中发挥关键作用。然而，尚不清楚与缺氧相关基因中的遗传变异在非小细胞肺癌 (NSCLC) 患者的生存中扮演何种角色。
我们评估了 182 个与缺氧相关基因中的 16092 个单核苷酸多态性 (SNP) 与 NSCLC 患者生存结局之间的关联。使用前列腺癌、肺癌、结直肠癌和卵巢癌 (PLCO) 癌症筛查试验的数据作为发现数据集，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。
鉴定出一个独立的 SNP，ERRFI1 rs28624 A>G，其对总生存期 (OS) 的调整后的危险比 (HR) 为 1.31 (95% CI = 1.14-1.51, p = 0.0001)。在进一步的分析中，与 AA 基因型相比，不利基因型 AC 和 CC 与更差的 OS (HR = 1.20, 95% CI = 1.03-1.39, p = 0.014) 和疾病特异性生存期 (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，ERRFI1 rs28624C 基因型与全血中 ERRFI1 mRNA 表达水平显著相关。进一步的分析表明，高 ERRFI1 mRNA 表达水平与肺腺癌患者的 OS 较差相关。
我们的研究结果表明，与缺氧相关基因 ERRFI1 中的遗传变异可能调节 NSCLC 的生存，可能是通过其对基因表达的影响。
