Potential Impacts of Interleukin-17A Promoter Polymorphisms on the EGFR Mutation Status and Progression of Non-Small Cell Lung Cancer in Taiwan

Abstract

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, p = 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; p = 0.020). In the WT EGFR subgroup analysis, IL-17A rs8193036 T-allele carriers had higher risks of developing an advanced tumor stage (p = 0.016) and lymphatic invasion (p = 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.

Genetic Associations of Visfatin Polymorphisms with EGFR Status and Clinicopathologic Characteristics in Lung Adenocarcinoma

“…Our observation that EGFR mutations are more common in females than males and in never-smokers than in ever-smokers among patients with LUAD is consistent with previous reports [ 6 , 29 ]. We also found that EGFR wild-type disease was more likely to exhibit poor cell differentiation and lower rates of well or moderate cell differentiation compared to EGFR -mutant disease, which is consistent with previous reports [ 12 , 13 ].…”

“…Given the important role of EGFR mutation status in NSCLC development, we decided to explore interactions amongst crucial genes and EGFR status in NSCLC and LUAD. Interleukin-17A, the tumor suppressor protein WW domain-containing oxidoreductase, tissue inhibitor of metalloproteinase 3 (TIMP3), and long noncoding RNA H19 polymorphisms have all been associated with clinicopathologic characteristics in lung cancers [ 5 , 9 , 12 , 13 ]. These four studies have helped to identify subgroups of patients at high risk for LUAD progression.…”

Evaluation of the clinical significance of long non-coding RNA MALAT1 genetic variants in human lung adenocarcinoma

“…In recent years, studies have also revealed that genetic polymorphisms of MALAT1 have susceptibility to cancers [ 31 , 32 , 40 ]. In our study, the cohort of LUAD demographics and fundamental traits were comparable to those of previous Asian cohort [ 48 , 49 ]; these cohort also showed that LUAD patients with an EGFR mutation were more likely to be female, never-smokers, and to have better cell differentiation than the EGFR wild-type group. The absence of smoking was linked to the development of LUAD, whereas EGFR mutations were more common among never-smoker ( Table 1 ).…”

The genomic landscape of the immune system in lung cancer: present insights and continuing investigations

“…A higher frequency of IL-17A rs8193037GA and AA genotypes has been linked to a predisposition to NSCLC, as having the rs8193037A allele was associated with higher production of IL-17 ( Cheng et al, 2015a ). Moreover, patients carrying the T-allele of IL-17A rs8193036(C > T) had a higher risk of developing advanced stages of LUAD than those having the CC genotype of rs8193036, probably through inducing the overexpression of IL-17A ( Lee et al, 2021 ). These studies suggest that polymorphisms that cause IL-17 overexpression are associated with increased susceptibility and enhanced lung tumor progression.…”