Genome-wide DNA methylation profiling reveals novel epigenetic signatures in squamous cell lung cancer

Shi, Yuan-Xiang; Wáng, Ying; Li, Xi; Zhang, Wei; Zhou, Hong‐Hao; Yin, Ji‐Ye; Liu, Zhao‐Qian

doi:10.1186/s12864-017-4223-3

Cited by 64 publications

(49 citation statements)

References 35 publications

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“…We have now identified 464 genes that are aberrantly methylated in SCC with or without IPF. Gene Ontology terms related to transcription and cell adhesion are enriched in these genes, in agreement with previous studies …”

Section: Discussionsupporting

confidence: 92%

“…Shi et al . identified more than 400 differentially methylated genes with altered expression in lung SCC, many of which are related to development and cell adhesion, and some were proposed as potential diagnostic markers.…”

Section: Discussionmentioning

confidence: 99%

“…Shi et al 30 identified more than 400 differentially methylated genes with altered expression in lung SCC, many of which are related to development and cell adhesion, and some were proposed as potential diagnostic markers. In addition, analysis of genome-wide methylation data in The Cancer Genome Atlas revealed several epigenotypes in SCC, 17 although the prognostic value of each, as well as their relationship to IPF, was not investigated.…”

Section: Discussionmentioning

confidence: 99%

“…Gene Ontology terms related to transcription and cell adhesion are enriched in these genes, in agreement with previous studies. 19,30 Aberrant promoter methylation in cancer is observed more frequently in genes targeted by the polycomb repressor complex in embryonic stem cells than in all other genes, suggesting that cancers arise from stem cells, via a mechanism in which reversible gene repression is replaced by permanent gene silencing. 31 Strikingly, genes targeted by both forms of polycomb repressor complex, that is, PRC1 and PRC2, 29 are significantly enriched in HME-specific markers and in markers common to both HME and LME, although PRC1 target genes are further enriched in common markers.…”

Section: Discussionmentioning

confidence: 99%

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

Hata

Nakajima

Matsusaka

et al. 2019

Intl Journal of Cancer

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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.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

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

Hata

Nakajima

Matsusaka

et al. 2019

Intl Journal of Cancer

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“…Furthermore, mutations in TP63 gene are rarely found in HNSCCs (39,40). However, silencing of TP63 gene expression through promoter methylation has been reported in lung and bladder cancer (41,42). In addition, in some nonsquamous tumor types, TP63 expression is downregulated by miRNAs (43,44).…”

Section: Discussionmentioning

confidence: 99%

Loss of TP63 Promotes the Metastasis of Head and Neck Squamous Cell Carcinoma by Activating MAPK and STAT3 Signaling

Lakshmanachetty

Balaiya

High

et al. 2019

Molecular Cancer Research

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TP63 is frequently amplified or overexpressed in primary head and neck squamous cell carcinomas (HNSCC). Nevertheless, the role of TP63 in the initiation and progression of HNSCCs is not known. Using archival HNSCC tissue sections, we found that TP63 expression is often downregulated in late-stage human HNSCCs. To establish a causal link between TP63 loss and HNSCC tumorigenesis, we developed a genetically engineered mouse model in which Trp63 (the mouse homolog of human TP63) was ablated from head and neck epithelia. Upon exposure of the mice to a chemical carcinogen, we found that Trp63 ablation accelerated HNSCC initiation and progression. To determine whether these findings are relevant for human HNSCCs, we generated TP63 knockdown HNSCC cell lines. These cells were implanted into the tongue of athymic nude mice to generate orthotopic xenografts. We found that loss of TP63 promoted HNSCC progression and metastasis. Furthermore, we determined that tumor metastasis is dependent on MAPK activation in TP63 knockdown HNSCCs. The significance of these findings is underscored by our finding that pharmacologic inhibition of MAPK activity by trametinib drastically impaired HNSCC metastasis mediated by TP63 loss. In conclusion, our data provide novel mechanistic insights into the role of TP63 loss in HNSCC initiation and progression, and provide a rationale for the development of new therapeutic approaches specifically targeting TP63-dependent tumor pathways.Implications: Our findings uncover a novel functional role for TP63 loss in HNSCC metastasis and identify MAPK signaling as a potential therapeutic target for treating HNSCCs with low TP63 expression.

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Identification and validation of novel DNA methylation markers for early diagnosis of lung adenocarcinoma

Zhang

Zhou

et al. 2020

Molecular Oncology

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Lung cancer has the highest mortality of all cancers worldwide. Epigenetic alterations have emerged as potential biomarkers for early diagnosis of various cancer tissue types. To identify methylation markers for early diagnosis of lung adenocarcinoma, we aimed to integrate genome-wide DNA methylation and gene expression data from The Cancer Genome Atlas. To this end, we first examined the global DNA methylation pattern of lung adenocarcinoma and investigated the relationship between DNA methylation subtypes and clinical features. We then extracted differentially methylated and expressed genes, and adopted feature selection techniques to determine the final methylation markers. The performance of the markers in predicting lung adenocarcinoma was evaluated on three independent datasets from Gene Expression Omnibus. Protein levels of marker genes were validated by immunohistochemistry, and their biological function was further verified in vivo. We identified three novel methylation markers in lung adenocarcinoma including cg08032924, cg14823851, and cg19161124, mapping to CMTM2, TBX4, and DPP6, respectively. Validating these results on three independent datasets indicated that the three markers can achieve extremely high sensitivity and specificity in distinguishing lung adenocarcinoma from normal samples. Immunohistochemistry quantification results confirmed that markers are weakly expressed in human lung adenocarcinoma, and CMTM2 decreased tumor growth of mouse Lewis lung carcinoma in vivo. Overall, our study identified three novel methylation markers in lung adenocarcinoma which may contribute toward an improved diagnosis potentially leading to a better outcome for patients with lung adenocarcinoma.

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Genome-wide DNA methylation profiling reveals novel epigenetic signatures in squamous cell lung cancer

Cited by 64 publications

References 35 publications

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

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

Loss of TP63 Promotes the Metastasis of Head and Neck Squamous Cell Carcinoma by Activating MAPK and STAT3 Signaling

Identification and validation of novel DNA methylation markers for early diagnosis of lung adenocarcinoma

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