Peroxisomes play a role in lipid metabolism and regulation of reactive oxygen species, but its role in development and progression of non-small cell lung cancer (NSCLC) is not well understood. Here, we investigated the associations between 9708 single-nucleotide polymorphisms (SNPs) in 113 genes in the peroxisome-related pathways and survival of NSCLC patients from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) and the Harvard Lung Cancer Susceptibility (HLCS) study. In 1185 NSCLC patients from the PLCO trial, we found that 213 SNPs were significantly associated with NSCLC overall survival (OS) (p ≤ 0.05, Bayesian false discovery probability [BFDP] ≤ 0.80), of which eight SNPs were validated in the HLCS data set. In a multivariate Cox proportional hazards regression model, two independent SNPs (rs9384742 DDO and rs9825224 PEX5L) were significantly associated with NSCLC survival (hazards ratios [HR] of 1.17 with 95% CI [confidence interval] of 1.06−1.28 and 0.86 with 95% CI of 0.77−0.96, respectively). Patients with one or two protective genotypes had a significantly higher OS (HR: 0.787 [95% CI: 0.620−0.998] and 0.691 [95% CI: 0.543−0.879], respectively). Further expression quantitative trait loci analysis using whole blood and lung tissue showed that the minor allele of rs9384742 DDO was significantly associated with decreased messenger RNA (mRNA) expression levels and that DDO expression was also decreased in NSCLC tumor tissue. Additionally, high PEX5L expression levels were significantly associated with lower survival of NSCLC. Our data suggest that variants in these peroxisome-related genes may influence gene regulation and are potential predictors of NSCLC OS, once validated by additional studies.

中文翻译：

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过氧化物酶体相关通路中 DDO 和 PEX5L 的遗传变异预测非小细胞肺癌的存活率

过氧化物酶体在脂质代谢和活性氧的调节中发挥作用，但其在非小细胞肺癌 (NSCLC) 的发展和进展中的作用尚不清楚。在这里，我们调查了过氧化物酶体相关通路中 113 个基因的 9708 个单核苷酸多态性 (SNP) 与来自前列腺癌、肺癌、结直肠癌和卵巢癌筛查试验 (PLCO) 和哈佛肺癌的 NSCLC 患者的存活率之间的关联易感性 (HLCS) 研究。在来自 PLCO 试验的 1185 名 NSCLC 患者中，我们发现 213 个 SNP 与 NSCLC 总生存期 (OS) 显着相关 ( p ≤ 0.05，贝叶斯错误发现概率 [BFDP] ≤ 0.80)，其中 8 个 SNP 在 HLCS 数据集中得到验证。在多变量 Cox 比例风险回归模型中，两个独立的 SNP（rs9384742 DDO和 rs9825224 PEX5L）与 NSCLC 生存显着相关（风险比 [HR] 为 1.17，95% CI [置信区间] 为 1.06-1.28 和 0.86，95% CI 分别为 0.77−0.96）。具有一种或两种保护性基因型的患者的 OS 显着更高（分别为 HR：0.787 [95% CI：0.620-0.998] 和 0.691 [95% CI：0.543-0.879]）。使用全血和肺组织进一步表达数量性状位点分析表明，rs9384742 DDO的次要等位基因与信使 RNA (mRNA) 表达水平降低显着相关，并且 NSCLC 肿瘤组织中DDO表达也降低。此外，高PEX5L表达水平与 NSCLC 的较低存活率显着相关。我们的数据表明，一旦通过其他研究验证，这些过氧化物酶体相关基因的变异可能会影响基因调控，并且是 NSCLC OS 的潜在预测因子。