Epigenetic reduction of DNA repair in progression to XXXX .

@entity5 @entity1 @entity14183 @entity1820
Deficiencies in DNA repair due to inherited germ-line mutations in DNA repair genes cause increased risk of @entity1820 . In @entity1820 , mutations in DNA repair genes are relatively rare. However, epigenetic alterations that reduce expression of DNA repair genes are frequent in @entity1820 . These epigenetic reductions are also found in field defects that give rise to @entity5 . Reduced DNA repair likely allows excessive DNA damages to accumulate in somatic cells. Then either inaccurate translesion synthesis past the un-repaired DNA damages or error-prone DNA repair can cause mutations. Erroneous DNA repair can also cause epigenetic alterations (i.e., epimutations, transmitted through multiple replication cycles). Some of these mutations and epimutations may cause progression to @entity5 . Thus, deficient or absent DNA repair is likely an important underlying cause of @entity5 . Whole genome sequencing of @entity1820 show that between thousands to hundreds of thousands of mutations occur in these @entity5 . Epimutations that reduce DNA repair gene expression and occur early in progression to @entity1820 are a likely source of this high genomic instability. @entity5 cells deficient in DNA repair are more vulnerable than normal cells to inactivation by DNA damaging agents. Thus, some of the most clinically effective chemotherapeutic agents in @entity5 treatment are DNA damaging agents, and their effectiveness often depends on @entity14183 in @entity5 cells. Recently, at least 18 DNA repair proteins, each active in one of six DNA repair pathways, were found to be subject to epigenetic reduction of expression in @entity1820 . Different DNA repair pathways repair different types of DNA damage. Evaluation of which DNA repair pathway(s) are @entity1820 and/or particular @entity1 may prove useful in guiding choice of therapeutic agents in @entity5 therapy.
