Causes and consequences of DNA hypomethylation in human cancer

Abstract

While specific genes are hypermethylated in the genome of cancer cells, overall methylcytosine content is often decreased as a consequence of hypomethylation affecting many repetitive sequences. Hypomethylation is also observed at a number of single-copy genes. While global hypomethylation is highly prevalent across all cancer types, it often displays considerable specificity with regard to tumor type, tumor stage, and sequences affected. Following an overview of hypomethylation alterations in various cancers, this review focuses on 3 hypotheses. First, hypomethylation at a single-copy gene may occur as a 2-step process, in which selection for gene function follows upon random hypo methylation. In this fashion, hypomethylation facilitates the adaptation of cancer cells to the ever-changing tumor tissue microenvironment, particularly during metastasis. Second, the development of global hypomethylation is intimately linked to chromatin restructuring and nuclear disorganization in cancer cells, reflected in a large number of changes in histone-modifying enzymes and other chromatin regulators. Third, DNA hypomethylation may occur at least partly as a consequence of cell cycle deregulation disturbing the coordination between DNA replication and activity of DNA methyltransferases. Finally, because of their relation to tumor progression and metastasis, DNA hypomethylation markers may be particularly useful to classify cancer and predict their clinical course.

Hypomethylation of LINE-1 and Alu in well-differentiated neuroendocrine tumors (pancreatic endocrine tumors and carcinoid tumors)

“…For example, hypomethylation is common in colon, liver, stomach, esophagus, lung, breast, head and neck, as well as urothelial and metastatic prostate carcinomas, but uncommon in renal cell carcinomas, papillary carcinomas of thyroid, lymphomas and most hematological malignancies. [25][26][27][28][29] This is also corroborated in experimental models of global hypomethylation in mice. The DNA methyltransferase-1 hypomorphic mice had suppression of polyp formation and reduction in the frequency of CpG island methylation in both the normal mucosa and adenomas in Apc (Min/ þ ) mice, but developed T-cell lymphomas and liver tumors.…”

“…In addition, hypomethylation was more frequent in LINE-1 than Alu sequences. Sitespecific differences in hypomethylation of repetitive sequences have been reported for normal tissue and tumors, histological type of tumor and different types of repetitive sequences (reviewed by Hoffman and Schulz 25 and Chalitchagorn et al 26 ). For example, hypomethylation is common in colon, liver, stomach, esophagus, lung, breast, head and neck, as well as urothelial and metastatic prostate carcinomas, but uncommon in renal cell carcinomas, papillary carcinomas of thyroid, lymphomas and most hematological malignancies.…”

Inviting instability: Transposable elements, double-strand breaks, and the maintenance of genome integrity

“…It is known, for example, that early developmental stages in mammalian species include a period of general hypomethylation across the genome [62]. Additionally, several forms of cancer are associated with a widespread hypomethylation [63]. Such hypomethylation may increase the transcriptional activity of these elements, thereby increasing the impact of transcriptional stress related DSBs.…”

Expression of methylation-related genes is associated with overall survival in patients with non-small cell lung cancer

“…Usually, neoplastic cells simultaneously exhibit global genomic hypomethylation and regionspecific hypermethylation. Most hypomethylation events in cancer cells appear to occur in repetitive and parasitic elements, which are heavily methylated in normal cells (Hoffmann and Schulz, 2005). These events may result in increased genomic instability.…”