text: As discussed by Jin and Roberston in their review, silencing of a DNA repair gene by hypermethylation may be a very early step in progression to cancer.  Such silencing is proposed to act similarly to a germ-line mutation in a DNA repair gene, and predisposes the cell and its descendants to progression to cancer.  Another review also indicated an early role for hypermethylation of DNA repair genes in cancer.  If a gene necessary for DNA repair is hypermethylated, resulting in deficient DNA repair, DNA damages will accumulate.  Increased DNA damage tends to cause increased errors during DNA synthesis, leading to mutations that can give rise to cancer.
  If hypermethylation of a DNA repair gene is an early step in carcinogenesis, then it may also occur in the normal-appearing tissues surrounding the cancer from which the cancer arose (the field defect).  See the table below.
  While DNA damages may give rise to mutations through error prone translesion synthesis, DNA damages can also give rise to epigenetic alterations during faulty DNA repair processes.  The DNA damages that accumulate due to hypermethylation of the promoters of DNA repair genes can be a source of the increased epigenetic alterations found in many genes in cancers.
  In an early study, looking at a limited set of transcriptional promoters, Fernandez et al. examined the DNA methylation profiles of 855 primary tumors.  Comparing each tumor type with its corresponding normal tissue, 729 CpG island sites (55% of the 1322 CpG island sites evaluated) showed differential DNA methylation.  Of these sites, 496 were hypermethylated (repressed) and 233 were hypomethylated (activated). Thus, there is a  high level of promoter methylation alterations in tumors.  Some of these alterations may contribute to cancer progression.