Roadmap for investigating epigenome deregulation and environmental origins of cancer.

The interaction between the (epi)genetic makeup of an individual and his/her environmental exposure record (exposome) is accepted as a determinant factor for a significant proportion of human malignancies. Recent evidence has highlighted the key role of epigenetic mechanisms in mediating gene-environment interactions and translating exposures into tumorigenesis. There is also growing evidence that epigenetic changes may be risk factor-specific ("fingerprints") that should prove instrumental in the discovery of new biomarkers in cancer. Here, we review the state of the science of epigenetics associated with environmental stimuli and cancer risk, highlighting key developments in the field. Critical knowledge gaps and research needs are discussed and advances in epigenomics that may help in understanding the functional relevance of epigenetic alterations. Key elements required for causality inferences linking epigenetic changes to exposure and cancer are discussed and how these alterations can be incorporated in carcinogen evaluation and in understanding mechanisms underlying epigenome deregulation by the environment.

Comparative genomic analysis of esophageal cancers.

The following, from the 12th OESO World Conference: Cancers of the Esophagus, includes commentaries on comparative genomic analysis of esophageal cancers: genomic polymorphisms, the genetic and epigenetic drivers in esophageal cancers, and the collection of data in the UK Barrett's Oesophagus Registry.

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

Cancers of the upper aerodigestive tract (UADT) are common forms of malignancy associated with tobacco and alcohol exposures, although human papillomavirus and nutritional deficiency are also important risk factors. While somatically acquired DNA methylation changes have been associated with UADT cancers, what triggers these events and precise epigenetic targets are poorly understood. In this study, we applied quantitative profiling of DNA methylation states in a panel of cancer-associated genes to a case-control study of UADT cancers. Our analyses revealed a high frequency of aberrant hypermethylation of several genes, including MYOD1, CHRNA3 and MTHFR in UADT tumors, whereas CDKN2A was moderately hypermethylated. Among differentially methylated genes, we identified a new gene (the nicotinic acetycholine receptor gene) as target of aberrant hypermethylation in UADT cancers, suggesting that epigenetic deregulation of nicotinic acetycholine receptors in non-neuronal tissues may promote the development of UADT cancers. Importantly, we found that sex and age is strongly associated with the methylation states, whereas tobacco smoking and alcohol intake may also influence the methylation levels in specific genes. This study identifies aberrant DNA methylation patterns in UADT cancers and suggests a potential mechanism by which environmental factors may deregulate key cellular genes involved in tumor suppression and contribute to UADT cancers.

Identification of a DNA methylome signature of esophageal squamous cell carcinoma and potential epigenetic biomarkers.

Esophageal squamous cell carcinoma (ESCC) is believed to arise from esophageal mucosa through accumulation of both genetic and epigenetic changes. DNA methylation is a critical epigenetic mechanism involved in key cellular processes and its deregulation has been linked to many human cancers, including ESCC. The aim of this study is to examine the global deregulation of methylation states in ESCC and identify potential early biomarkers. With this purpose, we performed a bead array analysis of more than 800 cancer-related genes in ten ESCC samples, ten matched surrounding tissues and four esophageal mucosa from healthy individuals. Pyrosequencing was used for validation of DNA methylation changes in up to 106 cases and 27 controls. A total of 37 CpG sites were found to be differentially methylated between tumors and surrounding tissues. These CpG sites were significantly enriched in genes related to several pathways including IL-10 anti-inflammatory signaling pathway and cell communication pathway. In addition, by comparing with healthy esophageal mucosa, we identified TFF1 gene as a potential early marker of ESCC. This is the first study to address methylation changes in ESCC in a large set of genes. Methylome analysis is shown as a sensitive and powerful tool to identify molecular players in ESCC. These data should prove to be the reference for future studies identifying potential biomarkers and molecular targets in ESCC.

Quantitative evaluation of SPRR3 expression in esophageal squamous cell carcinoma by qPCR and its potential use as a biomarker.

Esophageal squamous cell carcinoma (ESCC) is highly fatal due to late diagnosis and inefficient treatment. Early disease detection could improve diagnosis and patient survival. Esophageal squamous epithelial cells express SPRR3, a member of the small proline-rich protein family, which is downregulated in ESCC. Therefore, SPRR3 expression may be used as a biomarker to follow the transition from healthy mucosa to ESCC. Both SPRR3 mRNA splice variants, v1 and v2, were evaluated by real time PCR in tumor and histologically normal adjacent tissue biopsies from 84 ESCC patients and 18 healthy controls. SPRR3-v1 was most highly expressed in the esophageal mucosa of healthy subjects, with an increasingly lower expression in the adjacent mucosa of ESCC patients and in tumors, respectively. SPRR3-v2 expression was low in normal mucosa and in tumors but it was higher in the adjacent mucosa of ESCC patients. In addition, we found a significant correlation between a lower SPRR3-v1 and SPRR3-v2 expression and age and alcohol consumption, respectively. SPRR3 protein expression presented a good correlation with SPRR3 mRNA expression. Cut-off points to discriminate between healthy mucosa, tumor and adjacent mucosa were determined with receiver operating characteristic (ROC) curves. This analysis showed that SPRR3-v1 expression discriminates the esophageal mucosa of healthy subjects from the adjacent mucosa and the tumor of ESCC patients with high sensitivity and specificity. Our data shows that the quantitative analysis of SPRR3 mRNA is a robust and reliable method to monitor the malignant transformation of the healthy esophageal mucosa into ESCC.

Epigenetic signatures in cancer: Implications for the control of cancer in the clinic.

Significant progress in the field of cancer epigenetics has enhanced the understanding of epigenetic mechanisms in cellular processes and in abnormal events involved in tumorigenesis. Many studies have investigated epigenetic alterations in cancer cells and have revealed that epigenetic deregulation is important for the development of malignancy. These studies have also demonstrated that epigenetic changes are present in almost every human cancer, and that different cancers may harbor a specific 'epigenetic signature', which can be used for cancer control. This review focuses on studies that have revealed the existence of specific epigenetic changes related to particular cancer types and associated risk-factor exposures, and how these epigenetic signatures may be exploited in the diagnosis, treatment and prevention of cancer.