Comprehensive genomic and prognostic analysis of the IL-17 family genes in lung cancer

摘要

The six members of the interleukin (IL)-17 gene family (IL-17A-F) have been identified in various types of cancer. Although lung cancer is the leading cause of cancer-related death worldwide and IL-17A was found to play a critical role in lung cancer, there is little knowledge concerning the association between the other five members of the IL-17 family and lung cancer. The genetic mutations and expression of IL-17 family members were investigated using the Catalogue of Somatic Mutations in Cancer (COSMIC), Oncomine, and cBio Cancer Genomics Portal (cBioPortal) databases. Prognostic values and interaction networks of the members were assessed by the Kaplan-Meier plotter, Search Tool for the Retrieval of Interacting Genes (STRING) database and FunRich software. The results found that, across 5,238 lung cancer patients in the cBioPortal, the results of IL-17 family gene alteration frequencies and types showed that IL-17A, IL-25 and IL-17F exhibited higher alteration frequencies (2, 2.1 and 1.9%, respectively), and gene amplification accounted for the majority of changes. IL-17B, IL-17C and IL-17D exhibited lower alteration frequencies (0.8, 1.1 and 1.1%, respectively), and deep deletion accounted for the majority of changes. The rates of point mutations in IL-17A through IL-17F family genes in lung cancer were 0.66, 0.18, 0.13, 0.09, 0.27 and 0.44% in the COSMIC database. Within the Oncomine database, five datasets showed that IL-17D was significantly decreased in lung cancer, while no dataset showed a significant difference in the expression of IL-17A, IL-17B, IL-17C, IL-25 or IL17-F between lung cancer and normal controls. The frequencies of IL-17A, IL-17B and IL-17C mRNA upregulation in lung squamous cell carcinoma were lower than those in lung adenocarcinoma (2.7, 1.9 and 2.1%, respectively), whereas the frequencies of IL-17D, IL-25 and IL-17F mRNA upregulation were higher in lung squamous cell carcinoma than those in lung adenocarcinoma (3, 6 and 6%, respectively). IL-17A and IL-17B were unrelated to overall survival (p=0.11; P=0.17), whereas IL-17C, IL-17D, IL-25 and IL-17F influenced prognosis (P=0.0023, P=0.0059, P=0.039 and P=0.0017, respectively) according to the Kaplan-Meier plotter. Moreover, the expression level of IL-17C was the highest in lung tissues, and IL-17 family genes mainly participate in the IFN-gamma pathway' according to the STRING database and Funrich software. In conclusion, we performed the first comprehensive investigation of the IL-17 gene family in lung cancer, including gene mutation, mRNA expression levels, prognostic values and network pathways. Our results revealed that IL-17 family gene mutation rates were in general low and that amplification and deep deletion were the main mutation type. The expression and function of IL-17A and IL-17B in lung cancer are still not fully elucidated and warrant research with larger sample sizes. IL-17D was significantly decreased in lung cancer and was correlated with better OS. Studies of IL-17C-F in lung cancer are limited. Further experimental studies on the association between IL-17D and lung cancer progression are needed to identify more effective therapeutic targets for lung cancer.