Identification of common signatures in idiopathic pulmonary fibrosis and lung cancer using gene expression modeling

Dong Leng,Yuhui Zhang,Jiawen Yi,Hongying Zhao,Maodong Xiang

doi:10.1186/s12885-020-07494-w

Abstract

BackgroundIdiopathic pulmonary fibrosis (IPF) is associated with an increased risk for lung cancer, but the underlying mechanisms driving malignant transformation remain largely unknown. This study aimed to identify differentially expressed genes (DEGs) distinguishing IPF and lung cancer from healthy individuals and common genes driving the transformation from healthy to IPF and lung cancer.MethodsThe gene expression data for IPF and non-small cell lung cancer (NSCLC) were retrieved from the Gene Expression Omnibus (GEO) database. The DEG signatures were identified via unsupervised two-way clustering (TWC) analysis, supervised support vector machine analysis, dimensional reduction, and mutual exclusivity analysis. Gene enrichment and pathway analyses were performed to identify common signaling pathways. The most significant signature genes in common among IPF and lung cancer were further verified by immunohistochemistry.ResultsThe gene expression data from GSE24206 and GSE18842 were merged into a super array dataset comprising 86 patients with lung disorders (17 IPF and 46 NSCLC) and 51 healthy controls and measuring 23,494 unique genes. Seventy-nine signature DEGs were found among IPF and NSCLC. The peroxisome proliferator-activated receptor (PPAR) signaling pathway was the most enriched pathway associated with lung disorders, and matrix metalloproteinase-1 (MMP-1) in this pathway was mutually exclusive with several genes in IPF and NSCLC. Subsequent immunohistochemical analysis verified enhanced MMP1 expression in NSCLC associated with IPF.ConclusionsFor the first time, we defined common signature genes for IPF and NSCLC. The mutually exclusive sets of genes were potential drivers for IPF and NSCLC.

Highlights

Idiopathic pulmonary fibrosis (IPF) is associated with an increased risk for lung cancer, but the underlying mechanisms driving malignant transformation remain largely unknown
We aimed to identify common genes involved in both IPF and lung cancer by screening the gene expression omnibus (GEO) database for gene expression profile data of lung tissue samples from healthy controls as well as from patients with IPF and Non-small cell lung cancer (NSCLC)
As there is an ethnic difference for lung cancer but not for IPF, the GSE24206 (USA) and GSE18842 (Spain) datasets from Caucasians were compared to the GSE43346 (Japan) dataset from Asians; there was no appropriate dataset for small cell lung cancer (SCLC)

Summary

Introduction

Idiopathic pulmonary fibrosis (IPF) is associated with an increased risk for lung cancer, but the underlying mechanisms driving malignant transformation remain largely unknown. From a genetic point of view, lung cancer is a highly heterogenous disease with numerous somatic mutations. These driver alterations are capable of abnormally activating downstream signaling pathways and driving tumorigenesis by suppressing apoptosis and promoting cell proliferation, angiogenesis, invasion, and migration [9]. A recent genomic sequencing study demonstrated that IPF and lung cancer have some somatic mutations in common [12], but the genes driving the transformation from IPF to lung cancer are still unknown

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