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- Title
A low DNA methylation epigenotype in lung squamous cell carcinoma and its association with idiopathic pulmonary fibrosis and poorer prognosis.
- Authors
Hata, Atsushi; Nakajima, Takahiro; Matsusaka, Keisuke; Fukuyo, Masaki; Morimoto, Junichi; Yamamoto, Takayoshi; Sakairi, Yuichi; Rahmutulla, Bahityar; Ota, Satoshi; Wada, Hironobu; Suzuki, Hidemi; Matsubara, Hisahiro; Yoshino, Ichiro; Kaneda, Atsushi
- 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. What's new? The stratification of patients into risk subgroups can shed light on tumorigenic mechanisms and facilitate the development of tailored clinical strategies. Here, the authors explored the possibility of stratifying squamous cell carcinoma (SCC) of the lung based on methylation analysis of the SCC cell genome. Analyses successfully stratified SCC into two distinct epigenotypes, low methylation and high methylation. The low‐methylation epigenotype was significantly associated with idiopathic pulmonary fibrosis (IPF) and unfavorable outcome, suggesting that lung carcinogenesis follows distinct pathways in IPF patients. The findings further suggest that established methylation markers can be used to detect patients vulnerable to poor outcome.
- Subjects
SQUAMOUS cell carcinoma; DNA methylation; IDIOPATHIC pulmonary fibrosis; LUNGS; EMBRYONIC stem cells; HIERARCHICAL clustering (Cluster analysis); P16 gene
- Publication
International Journal of Cancer, 2020, Vol 146, Issue 2, p388
- ISSN
0020-7136
- Publication type
Article
- DOI
10.1002/ijc.32532