Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan.
Division of Pulmonary Medicine, Department of Internal Medicine, Taipei Medical University Hospital, Taipei 110301, Taiwan.
Genes (Basel). 2021 Mar 17;12(3):427. doi: 10.3390/genes12030427.
Non-small cell lung cancer (NSCLC) is a typical inflammation-associated cancer, and lung adenocarcinoma (LUAD) is the most common histopathological subtype. Epidermal growth factor receptor (EGFR) mutations are the most common driver mutations of LUAD, and they have been identified as important therapeutic targets by EGFR tyrosine kinase inhibitors. Interleukin (IL)-17A secreted by T-helper 17 lymphocytes is a proinflammatory cytokine that plays an important role in cancer pathogenesis. The present study was designed to investigate the possible associations among IL-17A genetic polymorphisms, EGFR mutation status, and the clinicopathologic development of LUAD in a Taiwanese population. Our study population consisted of 277 LUAD patients harboring the wild-type (WT) EGFR or a mutant (MT) EGFR. Four single-nucleotide polymorphisms (SNPs) of IL-17A in the peripheral blood, including rs8193036(C > T), rs8193037(G > A), rs2275913(G > A), and rs3748067(C > T) loci, were genotyped using a TaqMan allelic discrimination assay. Our results showed that none of these IL-17A SNPs were correlated with the risk of developing mutant EGFR. However, patients with a smoking habit who carried the GA genotype of IL-17A rs8193037 had a significantly lower susceptibility to EGFR mutations (adjusted odds ratio (AOR): 0.225; 95% confidence interval (CI): 0.056~0.900, = 0.035). Moreover, compared to individuals carrying the CC genotype of rs8193036 at IL-17A, T-allele carriers (CT + TT) were at higher risk of developing more-advanced stages (stage III or IV; = 0.020). In the WT EGFR subgroup analysis, IL-17A rs8193036 T-allele carriers had higher risks of developing an advanced tumor stage ( = 0.016) and lymphatic invasion ( = 0.049). Further analyses of clinical datasets revealed correlations of IL-17 receptor A (IL-17RA) and IL-17RC expressions with a poor prognosis of LUAD patients with a smoking history or with higher levels of tumor-infiltrating lymphocytes. In conclusion, our results suggested that two functional promoter polymorphisms of IL-17A, i.e., rs8193036 and rs8193037, were associated with the EGFR mutation status and progression in LUAD patients, indicating that these two genetic variants might act as possible markers for predicting patients' clinical prognoses.
非小细胞肺癌（NSCLC）是一种典型的炎症相关癌症，肺腺癌（LUAD）是最常见的组织病理学亚型。表皮生长因子受体（EGFR）突变是 LUAD 最常见的驱动突变，它们已被鉴定为 EGFR 酪氨酸激酶抑制剂的重要治疗靶点。T 辅助 17 淋巴细胞分泌的白细胞介素（IL）-17A 是一种促炎细胞因子，在癌症发病机制中发挥重要作用。本研究旨在探讨 IL-17A 遗传多态性、EGFR 突变状态与台湾人群 LUAD 的临床病理发展之间的可能关联。我们的研究人群包括 277 名携带野生型（WT）EGFR 或突变型（MT）EGFR 的 LUAD 患者。采用 TaqMan 等位基因鉴别检测法对 IL-17A 外周血中的 4 个单核苷酸多态性（SNP），包括 rs8193036（C>T）、rs8193037（G>A）、rs2275913（G>A）和 rs3748067（C>T）位点进行了基因分型。我们的结果表明，这些 IL-17A SNP 均与发生突变型 EGFR 的风险无关。然而，携带 IL-17A rs8193037 GA 基因型且有吸烟习惯的患者对 EGFR 突变的敏感性显著降低（调整后的优势比（AOR）：0.225；95%置信区间（CI）：0.056~0.900， = 0.035）。此外，与 IL-17A rs8193036 中的 CC 基因型相比，T 等位基因携带者（CT+TT）发生更晚期（III 或 IV 期）疾病的风险更高（ = 0.020）。在 WT EGFR 亚组分析中，IL-17A rs8193036 T 等位基因携带者发生晚期肿瘤的风险更高（ = 0.016）和淋巴管浸润的风险更高（ = 0.049）。对临床数据集的进一步分析显示，白细胞介素 17 受体 A（IL-17RA）和白细胞介素 17RC 的表达与有吸烟史或肿瘤浸润淋巴细胞水平较高的 LUAD 患者的不良预后相关。总之，我们的结果表明，IL-17A 的两个功能性启动子多态性，即 rs8193036 和 rs8193037，与 LUAD 患者的 EGFR 突变状态和进展相关，表明这两个遗传变异可能作为预测患者临床预后的潜在标志物。
