DNA methylation in cancer: too much, but also too little

Abstract

Cancer-associated DNA hypomethylation is as prevalent as cancer-linked hypermethylation, but these two types of epigenetic abnormalities usually seem to affect different DNA sequences. Much more of the genome is generally subject to undermethylation rather than overmethylation. Genomic hypermethylation in cancer has been observed most often in CpG islands in gene regions. In contrast, very frequent hypomethylation is seen in both highly and moderately repeated DNA sequences in cancer, including heterochromatic DNA repeats, dispersed retrotransposons, and endogenous retroviral elements. Also, unique sequences, including transcription control sequences, are often subject to cancer-associated undermethylation. The high frequency of cancer-linked DNA hypomethylation, the nature of the affected sequences, and the absence of associations with DNA hypermethylation are consistent with an independent role for DNA undermethylation in cancer formation or tumor progression. Increased karyotypic instability and activation of tumor-promoting genes by cis or trans effects, that might include altered heterochromatin-euchromatin interactions, may be important consequences of DNA hypomethylation which favor oncogenesis. The relationship of DNA hypomethylation to tumorigenesis is important to be considered in the light of cancer therapies involving decreasing DNA methylation. Inducing DNA hypomethylation may have short-term anticancer effects, but might also help speed tumor progression from cancer cells surviving the DNA demethylation chemotherapy.

Specific hypermethylation of LINE-1 elements during abnormal overgrowth and differentiation of human placenta

“…Keywords: DNA methylation; repetitive elements; human; partial hydatidiform mole (PHM); triploid diandric embryos; 5-methylcytosine antibody In somatic cells, DNA methylation patterns are stably inherited through mitosis. However, variations in the amount and distribution of methylated cytidines have been described in somatic cells during differentiation and aging (Issa, 2004) and a direct link between aberrant DNA methylation patterns and tumorigenic processes has been established (Ehrlich, 2002;Baylin, 2005).…”

“…On the other hand, tumorigenesis is also associated with a global reduction of 5-methylcytosine content (Ehrlich, 2002). This reduction can be attributed to repetitive sequences, which make up about 45% of the human genome (Rollins et al, 2006) and are frequently hypomethylated in tumors.…”

“…This reduction can be attributed to repetitive sequences, which make up about 45% of the human genome (Rollins et al, 2006) and are frequently hypomethylated in tumors. Low levels of DNA methylation have been found in the Alu (Weisenberger et al, 2005) and LINE-1 (Ehrlich, 2002) elements dispersed throughout the genome in cancer cells. In addition, satellite 2 (Sat2) sequences, predominantly localized in the juxtacentromeric heterochromatin of certain human chromosomes (Jeanpierre, 1994), and Sata, the major component of human centromeres (Lee et al, 1997), are also hypomethylated in cancer (Ehrlich, 2002).…”

“…Low levels of DNA methylation have been found in the Alu (Weisenberger et al, 2005) and LINE-1 (Ehrlich, 2002) elements dispersed throughout the genome in cancer cells. In addition, satellite 2 (Sat2) sequences, predominantly localized in the juxtacentromeric heterochromatin of certain human chromosomes (Jeanpierre, 1994), and Sata, the major component of human centromeres (Lee et al, 1997), are also hypomethylated in cancer (Ehrlich, 2002). Furthermore, quantitative analyses have suggested that the DNA methylation level of LINE-1, Alu and Sat2 repetitive sequences can be used as a surrogate marker for global methylation changes in cancer cells (Yang et al, 2004;Weisenberger et al, 2005).…”

Integration of ‘omics’ data in aging research: from biomarkers to systems biology

“…The epigenome is influenced by environmental and lifestyle factors (Nakajima et al ., 2010; Alegría‐Torres et al ., 2011; Breitling et al ., 2011) and is associated with many complex diseases such as neurodegenerative disorders (reviewed by Portela & Esteller, 2010) and cancer (Ehrlich, 2002; Horvath, 2013). Nearly 500 differentially methylated regions were found to be associated with chronological age and age‐related phenotypes such as lung function, cholesterol levels and maternal longevity (Bell et al ., 2012).…”