A low DNA methylation epigenotype in lung squamous cell carcinoma and its association with idiopathic pulmonary fibrosis and poorer prognosis

Abstract

Patients with idiopathic pulmonary fibrosis (IPF) have higher risk of developing lung cancer, for example, squamous cell carcinoma (SCC), and show poor prognosis, while the molecular basis has not been fully investigated. Here we conducted DNA methylome analysis of lung SCC using 20 SCC samples with/without IPF, and noncancerous lung tissue samples from smokers/nonsmokers, using Infinium HumanMethylation 450K array. SCC was clustered into low‐ and high‐methylation epigenotypes by hierarchical clustering analysis. Genes hypermethylated in SCC significantly included genes targeted by polycomb repressive complex in embryonic stem cells, and genes associated with Gene Ontology terms, for example, “transcription” and “cell adhesion,” while genes hypermethylated specifically in high‐methylation subgroup significantly included genes associated with “negative regulation of growth.” Low‐methylation subgroup significantly correlated with IPF (78%, vs. 17% in high‐methylation subgroup, p = 0.04), and the correlation was validated by additional Infinium analysis of SCC samples (n = 44 in total), and data from The Cancer Genome Atlas (n = 390). The correlation between low‐methylation subgroup and IPF was further validated by quantitative methylation analysis of marker genes commonly hypermethylated in SCC (HOXA2, HOXA9 and PCDHGB6), and markers specifically hypermethylated in high‐methylation subgroup (DLEC1, CFTR, MT1M, CRIP3 and ALDH7A1) in 77 SCC cases using pyrosequencing (p = 0.003). Furthermore, low‐methylation epigenotype significantly correlated with poorer prognosis among all SCC patients, or among patients without IPF. Multivariate analysis showed that low‐methylation epigenotype is an independent predictor of poor prognosis. These may suggest that lung SCC could be stratified into molecular subtypes with distinct prognosis, and low‐methylation lung SCC that significantly correlates with IPF shows unfavorable outcome.

Methylation in HOX Clusters and Its Applications in Cancer Therapy

“…Similarly, HOXA2 was found to exhibit distinct methylation profiles in at least four cancer sites: lung, colon/rectum, nasopharynx and bile duct [32,55,62,70,71]. In lung squamous cell carcinoma (SCC), HOXA2 was included in a panel of hypermethylated genes that might be useful to stratify SCC into molecular subtypes with distinct prognoses [70].…”

“…Similarly, HOXA2 was found to exhibit distinct methylation profiles in at least four cancer sites: lung, colon/rectum, nasopharynx and bile duct [ 32 , 55 , 62 , 70 , 71 ]. In lung squamous cell carcinoma (SCC), HOXA2 was included in a panel of hypermethylated genes that might be useful to stratify SCC into molecular subtypes with distinct prognoses [ 70 ]. It has been suggested that the HOXA2 methylation status, together with the methylation profile of other HOXA genes, may have prognostic value in laryngeal squamous cell carcinoma [ 105 ].…”

A risk score system based on DNA methylation levels and a nomogram survival model for lung squamous cell carcinoma

“…Low expression of ALDH7A1 in tumors of surgically treated patients with NScLc is associated with a decreased incidence of tumor recurrence, indicating that decreased expression of this gene may predict a good prognosis for these patients (33). Patients with LScc with idiopathic pulmonary fibrosis indicate a significantly decreased methylation level of ALDH7A1 compared with those without fibrosis (34). This observation suggests that methylation status of ALDH7A1 may affect other clinical factors.…”

Identification of Differentially Expressed Genes Triggered by Aberrant Methylation in Idiopathic Pulmonary Fibrosis Using Integrated Bioinformatic Analysis

“…In the study, we downloaded three gene expression pro les (GSE53845 [1], GSE92592 [2], and GSE124685 [3]) and two gene methylation pro les (GSE107226 and GSE121849 [4]) from Gene Expression Omnibus (GEO) database (https://www.ncbi.nlm.nih.gov/geo/).…”

“…For example, Atsushi Hata et al used methylation microarray sequencing to explore the methylation pro les of normal and brotic lung tissue. They found that the low-methylation subgroup signi cantly correlated with IPF [4]. However, so far there has not been any studies to analyze methylation patterns in pulmonary brosis on the gene expression pro le.…”