Editing CpG site (section)

=== Promoter CpG hyper/hypo-methylation in cancer ===

In cancers, loss of expression of genes occurs about 10 times more frequently by hypermethylation of promoter CpG islands than by mutations. For example, in a colorectal cancer there are usually about 3 to 6 [[Somatic evolution in cancer#Glossary|driver]] mutations and 33 to 66 [[Genetic hitchhiking|hitchhiker]] or passenger mutations.<ref name="pmid23539594">{{cite journal |vauthors=[[Bert Vogelstein|Vogelstein B]], Papadopoulos N, Velculescu VE, Zhou S, Diaz LA, Kinzler KW |title=Cancer genome landscapes |journal=Science |volume=339 |issue=6127 |pages=1546–58 |year=2013 |pmid=23539594 |pmc=3749880 |doi=10.1126/science.1235122 |bibcode=2013Sci...339.1546V }}</ref> In contrast, in one study of colon tumors compared to adjacent normal-appearing colonic mucosa, 1,734 CpG islands were heavily methylated in tumors whereas these CpG islands were not methylated in the adjacent mucosa.<ref name=Illingworth>{{cite journal |vauthors=Illingworth RS, Gruenewald-Schneider U, Webb S, Kerr AR, James KD, Turner DJ, Smith C, Harrison DJ, Andrews R, [[Adrian Bird|Bird AP]] |title=Orphan CpG islands identify numerous conserved promoters in the mammalian genome |journal=PLOS Genet. |volume=6 |issue=9 |pages=e1001134 |year=2010 |pmid=20885785 |pmc=2944787 |doi=10.1371/journal.pgen.1001134 |doi-access=free }}</ref> Half of the CpG islands were in promoters of annotated protein coding genes,<ref name=Illingworth /> suggesting that about 867 genes in a colon tumor have lost expression due to CpG island methylation. A separate study found an average of 1,549 differentially methylated regions (hypermethylated or hypomethylated) in the genomes of six colon cancers (compared to adjacent mucosa), of which 629 were in known promoter regions of genes.<ref name="pmid27493446">{{cite journal |vauthors=Wei J, Li G, Dang S, Zhou Y, Zeng K, Liu M |title=Discovery and Validation of Hypermethylated Markers for Colorectal Cancer |journal=Dis. Markers |volume=2016 |pages=1–7 |year=2016 |pmid=27493446 |pmc=4963574 |doi=10.1155/2016/2192853 |doi-access=free }}</ref> A third study found more than 2,000 genes differentially methylated between colon cancers and adjacent mucosa. Using [[gene set enrichment]] analysis, 569 out of 938 [[gene set enrichment|gene sets]] were hypermethylated and 369 were hypomethylated in cancers.<ref name="pmid23096130">{{cite journal |vauthors=Beggs AD, Jones A, El-Bahrawy M, El-Bahwary M, Abulafi M, Hodgson SV, Tomlinson IP |display-authors=6|title=Whole-genome methylation analysis of benign and malignant colorectal tumours |journal=J. Pathol. |volume=229 |issue=5 |pages=697–704 |year=2013 |pmid=23096130 |pmc=3619233 |doi=10.1002/path.4132 }}</ref> Hypomethylation of CpG islands in promoters results in overexpression of the genes or gene sets affected.

One 2012 study<ref name="pmid22389639">{{cite journal |vauthors=Schnekenburger M, Diederich M |title=Epigenetics Offer New Horizons for Colorectal Cancer Prevention |journal=Curr Colorectal Cancer Rep |volume=8 |issue=1 |pages=66–81 |year=2012 |pmid=22389639 |pmc=3277709 |doi=10.1007/s11888-011-0116-z }}</ref> listed 147 specific genes with colon cancer-associated hypermethylated promoters, along with the frequency with which these hypermethylations were found in colon cancers. At least 10 of those genes had hypermethylated promoters in nearly 100% of colon cancers. They also indicated 11 [[microRNA]]s whose promoters were hypermethylated in colon cancers at frequencies between 50% and 100% of cancers. MicroRNAs (miRNAs) are small endogenous RNAs that pair with sequences in [[messenger RNA]]s to direct post-transcriptional repression. On average, each microRNA represses several hundred target genes.<ref name="pmid18955434">{{cite journal |vauthors=Friedman RC, Farh KK, [[Christopher Burge|Burge CB]], [[David Bartel|Bartel DP]] |title=Most mammalian mRNAs are conserved targets of microRNAs |journal=Genome Res. |volume=19 |issue=1 |pages=92–105 |year=2009 |pmid=18955434 |pmc=2612969 |doi=10.1101/gr.082701.108 }}</ref> Thus microRNAs with hypermethylated promoters may be allowing over-expression of hundreds to thousands of genes in a cancer.

The information above shows that, in cancers, promoter CpG hyper/hypo-methylation of genes and of microRNAs causes loss of expression (or sometimes increased expression) of far more genes than does mutation.