{'fraction_non_alphanumeric': 0.013896037056098817, 'fraction_numerical': 0.0007720020586721565, 'mean_word_length': 5.403624382207578, 'pattern_counts': {'":': 0, '<': 0, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
The role of epigenetics in carcinogenesis

The impact of epigenetic alterations on the etiology and progression of tumors has been greatly underestimated by many scientists in the past. However, the community is now learning that genes are very frequently deregulated by means of epigenetics in tumor cell genomes and has also recognized that such epimutations might play as great of a role in carcinogenesis as classical DNA mutations do. During malignant transformation of a cell, massive methylation of gene regulatory sequences and massive demethylation of bulk DNA containing both other genes and repetitive DNA occur. These changes contribute to the pathomechanisms underlying tumor development: indeed, silencing of genes by hypermethylation of regulatory sequences is a further means of inactivating tumor suppressor genes, while activation of oncogenes may be caused by hypomethylation of the regulatory regions that were previously silenced. Demethylation and other epigenetic variations of repetitive-DNA-containing chromatin in neoplastic cells are thought to lead to less densely packed chromatin, which in turn would facilitate recombination events that become visible, such as chromosomal instability and highly rearranged karyotypes in tumor cells. In the special section of this issue of the International Journal of Cancer on epigenetics, Rojas et al. have successfully verified a hypothesis on the pathogenic role of a specific epimutation in colorectal cancer. While in this tumor entity, the high frequency of aberrant DNA methylation has been known for a long time, the biological effects of these epigenetic events have only recently been deciphered. The authors describe a frequent methylation of the gene coding for thrombospondin 1 (TSP1), which regulates activation of the TFG-beta pathway in colorectal adenocarcinomas, and provide conclusive evidence that silencing of the TSP1 gene by methylation is indeed a mechanism for suppressing TFG-beta signaling in this tumor type. In addition to their relevance for the pathomechanisms of cancer development, it is becoming increasingly clear that epimutations – just like DNA sequence variants – are associated with certain cancer risk groups in the human population. Actually, the effect of many environmental factors – which are reported in epidemiological studies to be associated with a certain risk for a given cancer type – on cell transformation might well be mediated by epimutations. The paper by Risch and Plass nicely summarizes the role of such epimutations in lung cancer, reviewing both the role of epimutations for the assessment of lung cancer risk groups and the role of epigenetic variations in the pathology of lung tumors. Furthermore, they discuss current methodologies to be used for respective screening strategies and provide a good perspective for developing an integrative approach to lung cancer research by combining epidemiology, genetics and epigenetics. One of the attractive features of DNA methylation as a factor responsible for tumor development is the fact that DNA methylation, unlike DNA mutations, has a high potential to be reverted in a directed manner. This has triggeredmultiple studies to develop drugs on the basis of, for example, DNAmethyl-transferase inhibition. The two most advanced drugs azacytidine and decitabine are currently being tested in multiple clinical trials. The paper by Stresemann and Lyko gives an expert summary of current knowledge of the pharmacological properties of these pro-drugs and offers a stimulating discussion on the mechanism of inhibition of DNAmethyl-transferases. Together with the guest editor of this special section, Manel Esteller, I wish to thank the authors for their valuable contributions and predict that we will see many more exciting publications in this area in the International Journal of Cancer in the near future.