The association between smoking and LINE-1 hypomethylation (global DNA hypomethylation) in normal esophageal epithelium of patients with esophageal squamous cell carcinoma.

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 41-41
Author(s):  
Shiro Iwagami ◽  
Yoshifumi Baba ◽  
Masayuki Watanabe ◽  
Hironobu Shigaki ◽  
Keisuke Miyake ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Squamous Cell Carcinoma ◽  
Esophageal Cancer ◽  
Squamous Cell ◽  
Methylation Level ◽  
Continuous Variable ◽  
Smoking History ◽  
Esophageal Mucosa ◽  
Esophageal Epithelium ◽  
Dna Hypomethylation

41 Background: DNA methylation is a major epigenetic mechanism in X-chromosome inactivation, imprinting and repression of transposable elements and endogenous retroviral sequences. Global DNA hypomethylation appears to play an important role in genomic instability, leading to cancer development. DNA methylation in the long interspersed nucleotide element-1, L1 (LINE-1) repetitive element is a good indicator of global DNA methylation level. Smoking and alcohol is extremely important as the etiology of esophageal squamous cell carcinoma. Nonetheless, whether or not smoking and alcohol affect LINE-1 methylation level in normal esophageal epithelium of esophageal cancer patients remains uncertain. Methods: We quantified LINE-1 methylation of normal esophageal mucosa using pyrosequencing technology in 118 resected esophageal squamous cell carcinomas. The data on smoking (Brinkman index, absence or presence) and alcohol amount are available in all cases. We excluded preoperatively treated cases. Results: LINE-1 methylation in normal esophageal epithelium of esophageal cancer patients ranged from 57.1 to 92.8 of 0-100 scale (N=118; mean 81.2; median 80.0; standard deviation 7.2). LINE-1 methylation level (continuous variable) was significantly associated with Brickman index (continuous variable) (r=0.12, p=0.0002); heavy smoker had lower LINE-1 methylation level of normal esophageal mucosa. LINE-1 methylation level was lower in patients with smoking history (mean 79.7) than in patients without smoking history (mean 83.2) (p=0.034). Alcohol assumption was not associated with LINE-1 methylation level (r=0.003, p=0.58). Conclusions: Smoking was associated with LINE-1 hypomethylation in esophageal normal epithelium, suggesting the possibility of epigenetic field effects caused by cigarette in esophageal tumorigenesis. Considering that DNA methylation alterations are reversible and can thus be targets for chemoprevention, our findings may have clinical implication.

Prognostic significance of LINE-1 methylation level in esophageal squamous cell carcinoma.

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 26-26 ◽  
Author(s):  
Yoshifumi Baba ◽  
Shiro Iwagami ◽  
Masayuki Watanabe ◽  
Hironobu Shigaki ◽  
Satoshi Ida ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Squamous Cell Carcinoma ◽  
Esophageal Cancer ◽  
Esophageal Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Methylation Level ◽  
Prognostic Significance ◽  
Esophageal Mucosa ◽  
Dna Hypomethylation

26 Background: Genome-wide DNA hypomethylation plays a role in genomic instability and carcinogenesis. DNA methylation in the long interspersed nucleotide element-1, L1 (LINE-1) repetitive element is a good indicator of global DNA methylation level. LINE-1 methylation is a useful marker for predicting cancer prognosis and monitoring efficacy of adjuvant therapy. Esophageal squamous cell carcinoma, the major histological type of esophageal cancer in East Asian countries, is one of the most aggressive malignant tumors. Nonetheless, prognostic significance of LINE-1 hypomethylaiton in esophageal cancer remains uncertain. Methods: Using 217 curatively resected esophageal squamous cell carcinomas, we quantified LINE-1 methylation using bisulfite-PCR-pyrosequencing assay. Cox proportional hazards model was used to calculate mortality hazard ratio (HR), adjusted for clinical, epidemiologic, and pathological variables. Results: Esophageal cancers showed significantly lower LINE-1 methylation level compared to matched normal esophageal mucosa (p<0.0001; N=50). Tumoral LINE-1 methylation ranged from 24.8 to 91.8 of 0-100 scale (N=217; mean 64.5; median 65.0; standard deviation 12.8). LINE-1 hypomethylation was significantly associated with disease-free survival [log-rank p=0.0008; univariate HR= 2.31, 95% confidence interval (CI) 1.38-3.84, p=0.0017; multivariate HR=1.81, 95% CI 1.06-3.05, p=0.031] and overall survival (log-rank p=0.0013; univariate HR=2.21, 95% CI 1.33-3.60, p=0.0026; multivariate HR=1.87, 95% CI 1.12-3.08, p=0.018]. Conclusions: LINE-1 hypomethylation in esophageal cancer is associated with shorter survival, suggesting its role as a prognostic biomarker. Given that epigenetic changes, including DNA methylation alterations, are reversible and can thus be targets for therapy or chemoprevention, our findings may have considerable clinical implications.

PS02.176: LINE-1 METHYLATION LEVEL AND LOCAL IMMUNE RESPONSE IN ESOPHAGEAL CANCER

2018 ◽  
Vol 31 (Supplement_1) ◽  
pp. 172-172
Author(s):  
Yoshifumi Baba ◽  
Taisuke Yagi ◽  
Yuki Kiyozumi ◽  
Yukiharu Hiyoshi ◽  
Masaaki Iwatsuki ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Immune Response ◽  
Esophageal Cancer ◽  
Methylation Level ◽  
Cpg Island ◽  
Surrogate Marker ◽  
Esophageal Tumor ◽  
Local Immune Response ◽  
Dna Hypomethylation ◽  
Response Status

Abstract Background In cancer cells, DNA methylation may be altered in two principle ways; global DNA hypomethylation and site-specific CpG island promoter hypermethylation. Since Long interspersed element-1 (LINE-1 or L1; a repetitive DNA retrotransposon) constitutes a substantial portion (approximately 17%) of the human genome, the extent of LINE-1 methylation is regarded as a surrogate marker of global DNA methylation. In previous studies, we demonstrated that LINE-1 hypomethylation was strongly associated with a poor prognosis in esophageal cancer, supporting its potential role as a prognostic marker (Ann Surg 2012). We also found that LINE-1-hypomethylated tumors showed highly frequent genomic gains at various loci containing candidate oncogenes such as CDK6 (Clin Cancer Res 2014). Given that immunotherapy, as represented by PD-1/PD-L1-targeting antibodies, has increasingly gained attention as a novel treatment strategy for esophageal cancer, better understanding of local immune response status in esophageal cancer is important. The aim of this study is to evaluate the relationship between LINE-1 methylation level and local immune response in esophageal cancer. Methods Using a non-biased database of 305 curatively resected esophageal cancers, we evaluated PD-L1 expression and TIL status (CD8 expression) by immunohistochemical analysis (Ann Surg 2017). Results TIL positivity was significantly correlated with longer overall survival (log-rank P < 0.0001). TIL-negative cases demonstrated significantly lower LINE-1 methylation level compared with TIL-positive cases (P = 0.012). This finding certainly supports that LINE-1 methylation level may influence the local immune response status. Conclusion PD-L1 expression was not related with LINE-1 methylation level. Further investigations in this field would provide deeper insights into esophageal tumor immunology and assist the development of new therapeutic strategies against esophageal cancer. Disclosure All authors have declared no conflicts of interest.

Global DNA Methylation Level in Whole Blood as a Biomarker in Head and Neck Squamous Cell Carcinoma

2007 ◽  
Vol 16 (1) ◽  
pp. 108-114 ◽  
Author(s):  
Debra Ting Hsiung ◽  
Carmen J. Marsit ◽  
E. Andres Houseman ◽  
Karen Eddy ◽  
C. Sloane Furniss ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Head And Neck ◽  
Squamous Cell ◽  
Whole Blood ◽  
Methylation Level ◽  
Neck Squamous Cell Carcinoma ◽  
Global Dna Methylation

scholarly journals Hypomethylation and downregulation of miR-23b-3p are associated with upregulated PLAU: a diagnostic and prognostic biomarker in head and neck squamous cell carcinoma

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Zirong Huo ◽  
Xiaoguang Li ◽  
Jieyu Zhou ◽  
Yuqin Fan ◽  
Zhentao Wang ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Head And Neck ◽  
Signaling Pathways ◽  
Squamous Cell ◽  
Prognostic Biomarker ◽  
Neck Squamous Cell Carcinoma ◽  
Dna Hypomethylation

Abstract Background DNA methylation and miRNA-target genes play an important part in the early development of various tumors and have been studied as tumor biomarkers. Although previous studies have reported a cluster of molecular events (such as aberrant alterations of genomics and epigenetics), little is known of the potential biomarkers for early diagnosis and prognostic evaluation in head and neck squamous cell carcinoma (HNSCC). Methods Multiple bioinformatics tools based on The Cancer Genome Atlas (TCGA) database and clinical samples were applied to evaluate the beneficial biomarkers in HNSCC. We focused on the role of plasminogen activator urokinase (PLAU), including diagnostic and prognostic significance, gene expression analysis, aberrant DNA methylation characteristics, interaction of miRNAs and associated signaling pathways. Results We found that PLAU was aberrantly upregulated in HNSCC, regardless of the mRNA or protein level. The results of receiver operating characteristic (ROC) curve and Cox regression analysis revealed that PLAU was a diagnostic and independent prognostic factor for patients with HNSCC. Hypomethylation of PLAU was closely related to poor survival in HNSCC. Additionally, miR-23b-3p was predicted to target PLAU and was significantly downregulated in HNSCC tissues. Therefore, our findings suggested that PLAU functioned as a promoter in the pathological process of HNSCC. DNA hypomethylation and downregulation of miR-23b-3p were associated with PLAU overexpression. Finally, our findings provided evidence of a significant interaction between PLAU-target and miRNAs-target pathways, indicating that miR-23b-3p suppresses malignant properties of HNSCC by targeting PLAU via Ras/MAPK and Akt/mTOR signaling pathways. Conclusions PLAU is overexpressed and may serve as an independent diagnostic and prognostic biomarker in HNSCC. Hypomethylation and downregulation of miR-23b-3p might account for the oncogenic role of PLAU in HNSCC.

scholarly journals Genetic Alterations of Esophageal Squamous Cell Carcinoma in Korean Patients

2021 ◽  
Author(s):  
Sunggyun Park ◽  
Dongju Won ◽  
Dae Joon Kim ◽  
Seong Yong Park ◽  
Seung-Tae Lee
Keyword(s):  
Squamous Cell Carcinoma ◽  
Esophageal Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Genetic Alterations ◽  
Small Sample ◽  
Smoking History ◽  
Base Substitution ◽  
Esophageal Mucosa ◽  
Sequencing Analysis

Abstract Background: Esophageal squamous cell carcinoma (ESCC) is one of the deadliest cancers in Korea, although its incidence is lower in Korea than in China and Japan. There are no data on genetic alterations associated with ESCC in Korea. Our study is the first report of the mutational landscape of ESCC in a Korean cohort.Methods: We performed whole exome sequencing analysis of 43 ESCC tumor samples and germline DNA from normal esophageal mucosa or whole blood. Using electronic medical records, the patients’ clinical characteristics were reviewed carefully.Results: We found a mutually exclusive mutation pattern in NFE2L2–ZNF750 gene pairs. Non-silent variants of KMT2D (MLL2) were associated with a poor prognosis. An analysis to identify potentially druggable genes revealed NOTCH1 as a potential therapeutic target. We observed a high frequency of C:G → T:A transitions regardless of smoking history. In our cohort, deconstruction of the mutation signature revealed enrichment of COSMIC single base substitution (SBS) 13, SBS 39, SBS 2, SBS 40, and SBS 1.Conclusion: We did not find a Korean-specific signature of genetic alterations, but our data suggest that KMT2D is a molecular prognostic marker. Further studies need to examine the role of KMT2D in ESCC prognosis due to our small sample size.

The DNA methylation landscape of PD-1 (PDCD1) and adjacent lncRNA AC131097.3 in head & neck squamous cell carcinoma

Epigenomics ◽  
2020 ◽  
Author(s):  
Christopher Bockhorst ◽  
Jörn Dietrich ◽  
Timo J Vogt ◽  
Roland H Stauber ◽  
Sebastian Strieth ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Neck Squamous Cell Carcinoma ◽  
Head Neck

scholarly journals Survivin in esophageal cancer: An accurate prognostic marker for squamous cell carcinoma but not adenocarcinoma

2006 ◽  
Vol 119 (7) ◽  
pp. 1717-1722 ◽  
Author(s):  
Antonio Rosato ◽  
Michela Pivetta ◽  
Anna Parenti ◽  
Gaetano A. Iaderosa ◽  
Alessia Zoso ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Esophageal Cancer ◽  
Cell Carcinoma ◽  
Prognostic Marker ◽  
Squamous Cell

scholarly journals Whole exome sequencing and deep sequencing of esophageal squamous cell carcinoma and adenocarcinoma in Japanese patients using the Japanese version of the Genome Atlas, JCGA

Esophagus ◽  
2021 ◽  
Author(s):  
Eisuke Booka ◽  
Yasuhiro Tsubosa ◽  
Tomoya Yokota ◽  
Shuhei Mayanagi ◽  
Kenjiro Ishii ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Esophageal Cancer ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Somatic Mutations ◽  
Molecular Targets ◽  
Japanese Version ◽  
Japanese Patients ◽  
Genetic Alterations ◽  
Genome Atlas

Abstract Background Recent comprehensive mutation analyses have revealed a relatively small number of driver mutations in esophageal cancer, implicating a limited number of molecular targets, most of which are also implicated in squamous cell carcinoma. Methods In this study, we investigated genetic alterations in 44 esophageal squamous cell carcinomas (ESCC) and 8 adenocarcinomas (EAC) from Japanese patients as potential molecular targets, based on data from the Japanese version of The Genome Atlas (JCGA). Results Esophageal cancer was characterized by TP53 somatic mutations in ESCC (39/44, 88.6%) and EAC (5/8, 62.5%). In addition to TP53 mutations, somatic mutations in NFE2L2 (16/44, 36.4%), CDKN2A (7/44, 15.9%), and KMT2D (7/44, 15.9%) were more frequently detected in ESCC than in EAC. WRN-truncated type mutations that lead to genomic instability correlate with EAC, but not ESCC. ESCC samples were enriched in ALDH2-associated mutational signature 16 as well as the APOBEC signature. Patients with FAT2 mutations had significantly poorer overall survival compared with those with wild-type status at FAT2 (p < 0.05). Patients with EP300 or PTPRD mutations also had poor progression-free survival compared with respective wild-types (p < 0.05 or p < 0.001). Conclusions These findings may facilitate future precision medicine approaches based on genomic profiling in ESCC and EAC.

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