DNA methylation changes associated with risk factors in tumors of the upper aerodigestive tract

Mani, Samson; Szymańska, Katarzyna; Cuenin, Cyrille; Заридзе, Давид; Balassiano, Karen Zavaro; Lima, Sheila Coelho Soares; Matos, Elena; Daudt, Alexander W.; Koifman, Sérgio; Filho, Victor Wünsch; Menezes, Ana; Curado, María Paula; Ferro, Gilles; Vaissière, Thomas; Sylla, Bakary S.; Tommasino, Massimo; Pinto, Luís Felipe Ribeiro; Boffetta, Paolo; Hainaut, Pierre; Brennan, Paul; Herceg, Zdenko

doi:10.4161/epi.7.3.19306

Cited by 20 publications

(17 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Targeting the Notch proliferation pathway is really difficult. Preliminary data in cell lines showed that downregulation of NOTCH1 in NOTCH1 mutant cell lines leads to a modest effect of cell cycle acceleration and anti- NOTCH1 agents are only effective in NOTCH1 wild type cell lines 40 . In our study, PAX1 was found to be the most frequently methylated and downregulated gene.…”

Section: Resultssupporting

confidence: 51%

Key tumor suppressor genes inactivated by “greater promoter” methylation and somatic mutations in head and neck cancer

et al. 2014

View full text Add to dashboard Cite

Tumor suppressor genes (TSGs) are commonly inactivated by somatic mutation and/or promoter methylation; yet, recent high-throughput genomic studies have not identified key TSGs inactivated by both mechanisms. We pursued an integrated molecular analysis based on methylation binding domain sequencing (MBD-seq), 450K Methylation arrays, whole exome sequencing, and whole genome gene expression arrays in primary head and neck squamous cell carcinoma (HNSCC) tumors and matched uvulopalatopharyngoplasty tissue samples (UPPPs). We uncovered 186 downregulated genes harboring cancer specific promoter methylation including PAX1 and PAX5 and we identified 10 key tumor suppressor genes (GABRB3, HOXC12, PARP15, SLCO4C1, CDKN2A, PAX1, PIK3AP1, HOXC6, PLCB1, and ZIC4) inactivated by both promoter methylation and/or somatic mutation. Among the novel tumor suppressor genes discovered with dual mechanisms of inactivation, we found a high frequency of genomic and epigenomic alterations in the PAX gene family of transcription factors, which selectively impact canonical NOTCH and TP53 pathways to determine cell fate, cell survival, and genome maintenance. Our results highlight the importance of assessing TSGs at the genomic and epigenomic level to identify key pathways in HNSCC, deregulated by simultaneous promoter methylation and somatic mutations.

show abstract

Section: Resultssupporting

confidence: 51%

Key tumor suppressor genes inactivated by “greater promoter” methylation and somatic mutations in head and neck cancer

et al. 2014

View full text Add to dashboard Cite

show abstract

“…Furthermore, this can increase the availability of 5,10-methylene THF for the synthesis of thymidine and purine, causing the hyper-proliferation of cancerous cells. In this regard, it was suggested that MTHFR hypermethylation might confer a growth advantage to cancer cells and contribute to the cancer phenotype in tumors of the upper aero-digestive tract [25]. Moreover, MTHFR promoter methylation levels have been correlated with cancer risk factors and with markers of impaired folate metabolism, including tobacco smoking, low circulating folates and vitamin B12, high homocysteine levels, and increased chromosome instability [15,18,26,27].…”

Section: Discussionmentioning

confidence: 99%

Gene-Specific Methylation Analysis in Thymomas of Patients with Myasthenia Gravis

Lopomo

Ricciardi

Maestri

et al. 2016

IJMS

View full text Add to dashboard Cite

Thymomas are uncommon neoplasms that arise from epithelial cells of the thymus and are often associated with myasthenia gravis (MG), an autoimmune disease characterized by autoantibodies directed to different targets at the neuromuscular junction. Little is known, however, concerning epigenetic changes occurring in thymomas from MG individuals. To further address this issue, we analyzed DNA methylation levels of genes involved in one-carbon metabolism (MTHFR) and DNA methylation (DNMT1, DNMT3A, and DNMT3B) in blood, tumor tissue, and healthy thymic epithelial cells from MG patients that underwent a surgical resection of a thymic neoplasm. For the analyses we applied the methylation-sensitive high-resolution melting technique. Both MTHFR and DNMT3A promoters showed significantly higher methylation in tumor tissue with respect to blood, and MTHFR also showed significantly higher methylation levels in tumor tissue respect to healthy adjacent thymic epithelial cells. Both DNMT1 and DNMT3B promoter regions were mostly hypomethylated in all the investigated tissues. The present study suggests that MTHFR methylation is increased in thymomas obtained from MG patients; furthermore, some degrees of methylation of the DNMT3A gene were observed in thymic tissue with respect to blood.

show abstract

“…This flexibility may contribute to disease risk by dysregulating gene expression in an exposure-specific manner (Feinberg 2007, 2008; Feinberg and Tycko 2004; Jones and Baylin 2002). Persistent effects of tobacco smoking on pulmonary (Bouloukaki et al 2011; Willemse et al 2005), cardiovascular (Conen et al 2011; Kawachi et al 1993) and malignant diseases (Mani et al 2012; Wilhelm-Benartzi et al 2011) have been widely observed and is indicative of epigenetic reprogramming. In particular, alterations in DNA methylation at both a global (Flom et al 2011; Furniss et al 2008; Smith et al 2007; Terry et al 2008) and locus-specific (Breitling et al 2011; Wan et al 2012) level have been associated with various diseases and are one potential mechanism mediating the adverse effects caused by smoking.…”

Section: Introductionmentioning

confidence: 99%

Epigenomic association analysis identifies smoking-related DNA methylation sites in African Americans

et al. 2013

View full text Add to dashboard Cite

Cigarette smoking is an environmental risk factor for many chronic diseases, and disease risk can often be managed by smoking control. Smoking can induce cellular and molecular changes, including epigenetic modification, but the short-term and long-term epigenetic modifications caused by cigarette smoking at the gene level have not been well understood. Recent studies have identified smoking-related DNA methylation (DNAm) sites in Caucasians. To determine whether the same DNAm sites associate with smoking in African Americans, and to identify novel smoking-related DNAm sites, we conducted a methylome-wide association study of cigarette smoking using a discovery sample of 972 African Americans, and a replication sample of 239 African Americans with two array-based methods. Among fifteen DNAm sites significantly associated with smoking after correction for multiple testing in our discovery sample, five DNAm sites are replicated in an independent cohort, and fourteen sites in the replication sample have effects in the same direction as in the discovery sample. The top two smoking-related DNAm sites in F2RL3 (factor II receptor-like 3) and GPR15 (G-protein-coupled receptor 15) observed in African Americans are consistent with previous findings in Caucasians. The associations between the replicated DNAm sites and smoking remain significant after adjusting for genetic background. Despite the distinct genetic background between African Americans and Caucasians, the DNAm from the two ethnic groups shares common associations with cigarette smoking, which suggests a common molecular mechanism of epigenetic modification influenced by environmental exposure.

show abstract

DNA methylation changes associated with risk factors in tumors of the upper aerodigestive tract

Cited by 20 publications

References 37 publications

Key tumor suppressor genes inactivated by “greater promoter” methylation and somatic mutations in head and neck cancer

Key tumor suppressor genes inactivated by “greater promoter” methylation and somatic mutations in head and neck cancer

Gene-Specific Methylation Analysis in Thymomas of Patients with Myasthenia Gravis

Epigenomic association analysis identifies smoking-related DNA methylation sites in African Americans

Contact Info

Product

Resources

About