PDF(Pubmed)
Abstract：
Prior research has proposed a potential association between lung cancer and inflammatory cytokines, yet the specific causal relationship remains unclear, especially across various lung cancer pathologies. This study utilized bidirectional Mendelian randomization (MR) to explore these causal connections, unveiling novel insights. Our research revealed distinctive inflammatory cytokine profiles for each subtype of lung cancer and identified potential biomarkers that could refine diagnostic and therapeutic approaches. We applied two-sample Mendelian randomization, leveraging genetic variance data from three extensive genome-wide association studies (GWAS) focusing on different lung cancer types (lung adenocarcinoma: 1590 cases and 314,193 controls of healthy individuals of European descent; lung squamous cell carcinoma: 1510 cases and 314,193 controls of European ancestry; small cell lung cancer: 717 cases and 314,193 controls of European ancestry). A separate GWAS summary on inflammatory cytokines from 8,293 healthy participants was also included. The inverse variance weighting method was utilized to examine causal relationships, with robustness confirmed through multiple sensitivity analyses, including MR-Egger, weighted median, and MR-PRESSO. Our analysis revealed that elevated levels of IL_1RA were associated with an increased risk of lung adenocarcinoma (OR: 1.29, 95% CI: 1.02-1.64, p = 0.031), while higher MCP_1_MCAF levels correlated with a decreased risk of lung squamous cell carcinoma (OR: 0.77, 95% CI: 0.61-0.98, p = 0.031). Furthermore, IL_10, IL_13, and TRAIL levels were positively associated with lung squamous cell carcinoma risk (IL_10: OR: 1.27, 95% CI: 1.06-1.53, p = 0.012; IL_13: OR: 1.15, 95% CI: 1.06-1.53, p = 0.036; TRAIL: OR: 1.15, 95% CI: 1.06-1.53, p = 0.043). No association was found between inflammatory cytokine levels and small cell lung cancer development, whereas SDF_1A and B-NGF were linked to an increased risk of this cancer type (SDF_1A: OR: 1.13, 95% CI: 1.05-1.21, p = 0.001; B-NGF: OR: 1.13, 95% CI: 1.01-1.27, p = 0.029). No significant relationship was observed between the 41 circulating inflammatory cytokines and lung adenocarcinoma or squamous cell carcinoma development. Our findings indicate distinct associations between specific inflammatory cytokines and different types of lung cancer. Elevated IL_1RA levels are a risk marker for lung adenocarcinoma, whereas higher MCP_1_MCAF levels appear protective against lung squamous cell carcinoma. Conversely, elevated levels of IL_10, IL_13, and TRAIL are linked with an increased risk of lung squamous cell carcinoma. The relationships of SDF_1A and B-NGF with small-cell lung cancer highlight the complexity of inflammatory markers in cancer development. This study provides a nuanced understanding of the role of inflammatory cytokines in lung cancer, underscoring their potential in refining diagnosis and treatment strategies.
摘要：
先前的研究提出了肺癌和炎症细胞因子之间的潜在关联，然而具体的因果关系仍不清楚，尤其是各种肺癌病理。这项研究利用双向孟德尔随机化(MR)来探索这些因果关系，揭示新颖的见解。我们的研究揭示了肺癌每种亚型的独特炎性细胞因子谱，并确定了可以改进诊断和治疗方法的潜在生物标志物。我们应用了两个样本孟德尔随机化，利用来自三项广泛的全基因组关联研究(GWAS)的遗传变异数据,重点关注不同类型的肺癌(肺腺癌:欧洲血统健康个体的1590例和314,193例对照;肺鳞状细胞癌:欧洲血统个体的1510例和314,193例对照;小细胞肺癌:欧洲血统个体的717例和314,193例对照).还包括来自8,293名健康参与者的炎性细胞因子的单独GWAS总结。利用方差逆加权法检验因果关系，通过多重敏感性分析证实了稳健性，包括MR-Egger,加权中位数，MR-PRESSO我们的分析显示，IL_1RA水平升高与肺腺癌的风险增加有关（OR：1.29，95％CI：1.02-1.64，p=0.031）。而较高的MCP_1_MCAF水平与肺鳞状细胞癌风险降低相关(OR:0.77,95%CI:0.61-0.98,p=0.031)。此外，IL_10、IL_13、TRAIL水平与肺鳞癌发病风险呈正相关(IL_10:OR:1.27,95%CI:1.06～1.53,p=0.012;IL_13:OR:1.15,95%CI:1.06～1.53,p=0.036;TRAIL:OR:1.15,95%CI:1.06～1.53,p=0.043)。炎性细胞因子水平与小细胞肺癌发展之间没有发现相关性，而SDF_1A和B-NGF与该类型癌症的风险增加相关(SDF_1A:OR:1.13,95%CI:1.05-1.21,p=0.001;B-NGF:OR:1.13,95%CI:1.01-1.27,p=0.029)。在41种循环炎性细胞因子与肺腺癌或鳞状细胞癌的发展之间没有观察到显着关系。我们的发现表明特定的炎症细胞因子与不同类型的肺癌之间存在明显的关联。IL_1RA水平升高是肺腺癌的风险标志物，而较高的MCP_1_MCAF水平似乎对肺鳞状细胞癌具有保护作用。相反，IL_10，IL_13和TRAIL水平升高与肺鳞状细胞癌的风险增加有关。SDF_1A和B-NGF与小细胞肺癌的关系突出了肿瘤发展中炎症标志物的复杂性。这项研究提供了对炎症细胞因子在肺癌中的作用的细致理解。强调他们在完善诊断和治疗策略方面的潜力。
