Epigenetics of lung cancer

Langevin, Scott M.; Kratzke, Robert A.; Kelsey, Karl T.

doi:10.1016/j.trsl.2014.03.001

Cited by 140 publications

(123 citation statements)

References 259 publications

(239 reference statements)

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“…Promoter hypermethylation of individual genes, notably tumor suppressors like CDKN2A, have been recognized as early events in lung tumorigenesis, while there is a lack of consensus over whether global hypomethylation is an early or late event in lung cancer (see refs. 37,38). The impact of smoking on epigenetic modifications may further complicate the picture, as certain alterations have been associated with duration or amount of tobacco smoking and may thus be later events in the cancer development and progression (38).…”

Section: Discussionmentioning

confidence: 99%

“…37,38). The impact of smoking on epigenetic modifications may further complicate the picture, as certain alterations have been associated with duration or amount of tobacco smoking and may thus be later events in the cancer development and progression (38). Whole-genome bisulfite sequencing combined with other profiling/sequencing techniques may be one potential way of reconstructing the evolution of a tumor in relation to driver mutations, CNAs, and DNA methylation, as recently described for DNA alterations in breast cancer (47).…”

Section: Discussionmentioning

confidence: 99%

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Genome-wide DNA Methylation Analysis of Lung Carcinoma Reveals One Neuroendocrine and Four Adenocarcinoma Epitypes Associated with Patient Outcome

Karlsson

Jönsson

Lauss

et al. 2014

Clinical Cancer Research

129

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Purpose: Lung cancer is the worldwide leading cause of death from cancer. DNA methylation in gene promoter regions is a major mechanism of gene expression regulation that may promote tumorigenesis. However, whether clinically relevant subgroups based on DNA methylation patterns exist in lung cancer remains unclear.Experimental Design: Whole-genome DNA methylation analysis using 450K Illumina BeadArrays was performed on 12 normal lung tissues and 124 tumors, including 83 adenocarcinomas, 23 squamous cell carcinomas (SqCC), 1 adenosquamous cancer, 5 large cell carcinomas, 9 large cell neuroendocrine carcinomas (LCNEC), and 3 small-cell carcinomas (SCLC). Unsupervised bootstrap clustering was performed to identify DNA methylation subgroups, which were validated in 695 adenocarcinomas and 122 SqCCs. Subgroups were characterized by clinicopathologic factors, whole-exome sequencing data, and gene expression profiles.Results: Unsupervised analysis identified five DNA methylation subgroups (epitypes). One epitype was distinctly associated with neuroendocrine tumors (LCNEC and SCLC). For adenocarcinoma, remaining four epitypes were associated with unsupervised and supervised gene expression phenotypes, and differences in molecular features, including global hypomethylation, promoter hypermethylation, genomic instability, expression of proliferation-associated genes, and mutations in KRAS, TP53, KEAP1, SMARCA4, and STK11. Furthermore, these epitypes were associated with clinicopathologic features such as smoking history and patient outcome.Conclusions: Our findings highlight one neuroendocrine and four adenocarcinoma epitypes associated with molecular and clinicopathologic characteristics, including patient outcome. This study demonstrates the possibility to further subgroup lung cancer, and more specifically adenocarcinomas, based on epigenetic/molecular classification that could lead to more accurate tumor classification, prognostication, and tailored patient therapy. Clin Cancer Res; 20(23); 6127-40. Ó2014 AACR.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Genome-wide DNA Methylation Analysis of Lung Carcinoma Reveals One Neuroendocrine and Four Adenocarcinoma Epitypes Associated with Patient Outcome

Karlsson

Jönsson

Lauss

et al. 2014

Clinical Cancer Research

129

View full text Add to dashboard Cite

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“…These, and other modifications, generate a combinatorial histone code that demarcates chromatin regions for transcription activation or repression. Recently, cellular patterns of histone modifications have been demonstrated to be prognostic indicators for numerous types of tumors, including prostate (6), kidney (7), lung (8), gastric (9), ovarian (10) and breast cancer (11); however, little is known about the global alteration of histone status during tumorigenesis, and cancer progression in endometrial cancer. The present study therefore aimed to assess the clinical significance of selected histone modifications in endometrial tissues, including the normal endometrium, precancerous lesions and endometrial cancer.…”

Section: Introductionmentioning

confidence: 99%

The expression and significance of histone lysine methylation in endometrial cancer

Nan

Tao

et al. 2017

Oncol Lett

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Abstract. Histone modifications of lysine residues have been implicated as having diagnostic and/or prognostic significance in numerous types of cancer. In the present study, the significance of the histone H3 methylation of lysine 4 (H3K4) and lysine 27 (H3K27) were investigated in endometrial cancer. Specifically, immunohistochemical analysis was used to detect the cellular expression levels of H3K27 trimethylation (H3K27me3), H3K4 trimethylation (H3K4me3) and H3K4 dimethylation (H3K4me2) in glandular epithelial tissues and stromal tissues. The association between the methylation levels of histone markers and clinicopathological parameters were analyzed. The results demonstrated that in epithelial cells, H3K4me2 and H3K4me3 exhibited the highest levels in endometrial cancer, followed by precancerous lesions and a normal endometrium. Low expression levels of H3K4me2 in glandular epithelium of endometrial cancer were significantly associated with a clinical early International Federation of Gynecology and Obstetrics stage (P= 0.006). For stromal tissues, the expression level of H3K27me3 in Type 1 endometrial cancer was significantly lower compared with that in the normal endometrium (P= 0.043) and precancerous lesions (P<0.001). The expression level of H3K4me2 was significantly lower in the stroma of Type 1 and 2 cancer compared within the normal endometrium (P= 0.005). A low H3K4me3 expression level in the stroma of endometrial cancer tissues was associated with P53-negativity (P= 0.032). In conclusion, the cellular expression levels of histone H3 methylation were differentially presented in glandular epithelial and stromal elements in endometrial tissues. A low expression level of activation marker H3K4me2 in glandular epithelium defined a subset of patients with early-stage endometrial adenocarcinoma and may have potential prognostic value.

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“…alterations, including DNA methylation, histone modifications, and non-coding RNA expression, have widely been reported in the literature to play a major role in the genesis of lung cancer (Langevin, Kratzke, & Kelsey, 2015). DNA methylation is the most studied epigenetic regulatory mechanism (Ansari, Shackelford, & El-Osta, 2016), Epigenetic alterations, such as aberrant DNA methylation, are deeply involved in human cancer development (Kalari & Pfeifer, 2010; Y.-C. Lee et al, 2011), Especially, aberrant DNA methylation of a CpG island (CGI) in a promoter region causes silencing of its downstream gene and is known as a major mechanism for inactivation of tumor suppressor genes in human lung cancers (Esteller, 2002;Risch & Plass, 2008).…”

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confidence: 99%

Assessing Gene Expression and Methylation of KMT2D and IGF2 Genes in Patients with Non-Small Cell Lung Cancer

Ahmadi

Ghasemi

Nooshin

et al. 2018

CCO

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Background: Aberrant promoter methylation of CpG islands is an important mechanism for regulation of gene expression. Recent data suggest that epigenetic abnormalities may occur very early in lung carcinogenesis. Systemic methylation changes may be a diagnostic marker for tumor development or prognosis. In this study, the expression and methylation of KMT2D and IGF2 genes were investigated in the lung cancer tissue compared to the adjacent normal tissue. Methods:The status of methylation of KMT2D and IGF2 genes were investigated in 30 patients with NSCLC after genomic DNA extraction using bisulfite treatment and MS-HRM method and the expression of these genes were checked by Real-Time PCR method in same samples.Results: For KMT2D gene, the expression and methylation level increased in 46.6% and 6.67% (respectively) for tumor samples comparison with normal samples (P>0.05). Also, for IGF2 gene 50% tumor samples overexpressed and 50% tumor samples showed that reduced expression comparison with the normal samples (P>0.05). In addition, 96.66% of tumor tissues did not show any change in methylation level for IGF2 gene promoter (P>0.05). Conclusion:This study showed that expression and methylation level of KMT2D and IGF2 genes did not change in NSCLC tumor samples compared to normal samples. However, this study was designed as a pilot study, and further investigations are required to confirm our findings.

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Epigenetics of lung cancer

Cited by 140 publications

References 259 publications

Genome-wide DNA Methylation Analysis of Lung Carcinoma Reveals One Neuroendocrine and Four Adenocarcinoma Epitypes Associated with Patient Outcome

Genome-wide DNA Methylation Analysis of Lung Carcinoma Reveals One Neuroendocrine and Four Adenocarcinoma Epitypes Associated with Patient Outcome

The expression and significance of histone lysine methylation in endometrial cancer

Assessing Gene Expression and Methylation of KMT2D and IGF2 Genes in Patients with Non-Small Cell Lung Cancer

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