Editing Malignant transformation (section)

====Transcription silencing====

A second underlying commonality in cancers is altered [[Cancer epigenetics|epigenetic]] [[regulation of transcription in cancer|regulation of transcription]].  In cancers, loss of [[gene expression]] occurs about 10 times more frequently by epigenetic transcription silencing (caused, for example, by [[DNA methylation in cancer#Methylation of CpG islands in promoters stably silences genes|promoter hypermethylation of CpG islands]]) than by mutations.  As Vogelstein et al.<ref name="pmid23539594"/> point out, 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"/>  In contrast, the frequency of [[Cancer epigenetics|epigenetic]] alterations is much higher.  In colon tumors compared to adjacent normal-appearing colonic mucosa, there are about 600 to 800 heavily methylated [[DNA methylation#CpG islands|CpG islands]] in [[promoter (genetics)|promoter]]s of genes in the tumors while the corresponding CpG islands are 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, 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><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><ref name=Beggs>{{cite journal |vauthors=Beggs AD, Jones A, El-Bahrawy M, El-Bahwary M, Abulafi M, Hodgson SV, Tomlinson IP |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>  Such methylation turns off expression of a gene as completely as a mutation would.  Around 60–70% of human genes have a CpG island in their promoter region.<ref>{{Cite journal|last1=Illingworth|first1=Robert S.|last2=Gruenewald-Schneider|first2=Ulrike|last3=Webb|first3=Shaun|last4=Kerr|first4=Alastair R. W.|last5=James|first5=Keith D.|last6=Turner|first6=Daniel J.|last7=Smith|first7=Colin|last8=Harrison|first8=David J.|last9=Andrews|first9=Robert|date=2010-09-23|title=Orphan CpG Islands Identify Numerous Conserved Promoters in the Mammalian Genome|journal=PLOS Genetics|volume=6|issue=9|pages=e1001134|doi=10.1371/journal.pgen.1001134|issn=1553-7404|pmc=2944787|pmid=20885785 |doi-access=free }}</ref><ref>{{Cite journal|last1=Saxonov|first1=Serge|last2=Berg|first2=Paul|last3=Brutlag|first3=Douglas L.|date=2006-01-31|title=A genome-wide analysis of CpG dinucleotides in the human genome distinguishes two distinct classes of promoters|journal=Proceedings of the National Academy of Sciences|language=en|volume=103|issue=5|pages=1412–1417|doi=10.1073/pnas.0510310103|issn=0027-8424|pmc=1345710|pmid=16432200|bibcode=2006PNAS..103.1412S |doi-access=free}}</ref>  In colon cancers, in addition to hypermethylated genes, several hundred other genes have hypomethylated (under-methylated) promoters, thereby causing these genes to be turned on when they ordinarily would be turned off.<ref name=Beggs />