Editing Malignant transformation (section)

===Epigenetic alterations===

====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 />

====Post-transcriptional silencing====

Epigenetic alterations are also carried out by another major regulatory element, that of [[microRNA]]s (miRNAs).  In mammals, these small [[non-coding RNA]] molecules regulate about 60% of the [[gene transcription|transcriptional]] activity of protein-encoding genes.<ref name="pmid18955434">{{cite journal | last1=Friedman |first1=RC |last2=Farh |first2=KK |last3=Burge |first3=CB |last4=Bartel |first4=DP | title = Most mammalian mRNAs are conserved targets of microRNAs | journal = Genome Res. | volume = 19 | issue = 1 | pages = 92–105 |date=January 2009 | pmid = 18955434 | pmc = 2612969 | doi = 10.1101/gr.082701.108}}</ref>  Epigenetic silencing or epigenetic over-expression of miRNA genes, caused by aberrant DNA methylation of the promoter regions controlling their expression, is a frequent event in cancer cells.  Almost one third of miRNA promoters active in normal mammary cells were found to be hypermethylated in breast cancer cells, and that is a several fold greater proportion of promoters with altered methylation than is usually observed for protein coding genes.<ref>{{cite journal|last1=Vrba |first1=L |last2=Muñoz-Rodríguez |first2=JL |last3=Stampfer |first3=MR |last4=Futscher |first4=BW |year=2013 |title=miRNA Gene Promoters Are Frequent Targets of Aberrant DNA Methylation in Human Breast Cancer. |journal=PLOS ONE |volume=8 |number=1 |page=e54398 |doi=10.1371/journal.pone.0054398 |pmid=23342147 |pmc=3547033|bibcode=2013PLoSO...854398V |doi-access=free }}</ref>  Other microRNA promoters are hypomethylated in breast cancers, and, as a result, these microRNAs are over-expressed.  Several of these over-expressed microRNAs have a major influence in progression to breast cancer.  [[BRCA1]] is normally expressed in the cells of [[breast]] and other tissue, where it helps repair damaged [[DNA]], or destroy cells if DNA cannot be repaired.<ref name="pmid12052432">{{cite journal |vauthors=Bernstein C, Bernstein H, Payne CM, Garewal H |title=DNA repair/pro-apoptotic dual-role proteins in five major DNA repair pathways: fail-safe protection against carcinogenesis |journal=Mutat. Res. |volume=511 |issue=2 |pages=145–78 |year=2002 |pmid=12052432 |doi= 10.1016/s1383-5742(02)00009-1|bibcode=2002MRRMR.511..145B }}</ref>  BRCA1 is involved in the repair of [[chromosome|chromosomal]] damage with an important role in the error-free [[DNA repair|repair of DNA]] double-strand breaks.<ref name="pmid17683622">{{cite journal |vauthors=Friedenson B |title=The BRCA1/2 pathway prevents hematologic cancers in addition to breast and ovarian cancers |journal=BMC Cancer |volume=7 |pages=152 |year=2007 |pmid=17683622 |pmc=1959234 |doi=10.1186/1471-2407-7-152 |doi-access=free }}</ref>  [[BRCA1]] expression is reduced or undetectable in the majority of high grade, ductal breast cancers.<ref name="pmid9988281">{{cite journal |vauthors=Wilson CA, Ramos L, Villaseñor MR, Anders KH, Press MF, Clarke K, Karlan B, Chen JJ, Scully R, Livingston D, Zuch RH, Kanter MH, Cohen S, Calzone FJ, Slamon DJ |title=Localization of human BRCA1 and its loss in high-grade, non-inherited breast carcinomas |journal=Nat. Genet. |volume=21 |issue=2 |pages=236–40 |year=1999 |pmid=9988281 |doi=10.1038/6029 |s2cid=7988460 }}</ref>  Only about 3–8% of all women with breast cancer carry a mutation in BRCA1 or BRCA2.<ref name="pmid9653432">{{cite journal |vauthors=Brody LC, Biesecker BB |title=Breast cancer susceptibility genes. BRCA1 and BRCA2 |journal=Medicine (Baltimore) |volume=77 |issue=3 |pages=208–26 |year=1998 |pmid=9653432 |doi= 10.1097/00005792-199805000-00006|doi-access=free }}</ref>  ''BRCA1'' [[DNA methylation|promoter hypermethylation]] was present in only 13% of unselected primary breast carcinomas.<ref name="pmid10749912">{{cite journal |vauthors=Esteller M, Silva JM, Dominguez G, Bonilla F, Matias-Guiu X, Lerma E, Bussaglia E, Prat J, Harkes IC, Repasky EA, Gabrielson E, Schutte M, Baylin SB, Herman JG|author-link13=Stephen B. Baylin|author-link14=James G. Herman |title=Promoter hypermethylation and BRCA1 inactivation in sporadic breast and ovarian tumors |journal=J. Natl. Cancer Inst. |volume=92 |issue=7 |pages=564–9 |year=2000 |pmid=10749912 |doi= 10.1093/jnci/92.7.564|doi-access=free }}</ref>   However, breast cancers were found to have an average of about 100-fold increase in miR-182, compared to normal breast tissue.<ref name="pmid23249749">{{cite journal |vauthors=Krishnan K, Steptoe AL, Martin HC, Wani S, Nones K, Waddell N, Mariasegaram M, Simpson PT, Lakhani SR, Gabrielli B, Vlassov A, Cloonan N, Grimmond SM |title=MicroRNA-182-5p targets a network of genes involved in DNA repair |journal=RNA |volume=19 |issue=2 |pages=230–42 |year=2013 |pmid=23249749 |pmc=3543090 |doi=10.1261/rna.034926.112 }}</ref>  In breast cancer cell lines, there is an inverse correlation of [[BRCA1]] protein levels with miR-182 expression.<ref name=Moskwa>{{cite journal |vauthors=Moskwa P, Buffa FM, Pan Y, Panchakshari R, Gottipati P, Muschel RJ, Beech J, Kulshrestha R, Abdelmohsen K, Weinstock DM, Gorospe M, Harris AL, Helleday T, Chowdhury D |title=miR-182-mediated downregulation of BRCA1 impacts DNA repair and sensitivity to PARP inhibitors |journal=Mol. Cell |volume=41 |issue=2 |pages=210–20 |year=2011 |pmid=21195000 |pmc=3249932 |doi=10.1016/j.molcel.2010.12.005 }}</ref> Thus it appears that much of the reduction or absence of BRCA1 in high grade ductal breast cancers may be due to over-expressed miR-182.  In addition to miR-182, a pair of almost identical microRNAs, miR-146a and miR-146b-5p, also repress BRCA1 expression.  These two microRNAs are over-expressed in triple-negative tumors and their over-expression results in BRCA1 inactivation.<ref name="pmid21472990">{{cite journal |vauthors=Garcia AI, Buisson M, Bertrand P, Rimokh R, Rouleau E, Lopez BS, Lidereau R, Mikaélian I, Mazoyer S |title=Down-regulation of BRCA1 expression by miR-146a and miR-146b-5p in triple negative sporadic breast cancers |journal=EMBO Mol Med |volume=3 |issue=5 |pages=279–90 |year=2011 |pmid=21472990 |pmc=3377076 |doi=10.1002/emmm.201100136 }}</ref>  Thus, miR-146a and/or miR-146b-5p may also contribute to reduced expression of BRCA1 in these triple-negative breast cancers.

[[Post-transcriptional regulation#MicroRNA mediated regulation|Post-transcriptional regulation]] by microRNA occurs either through translational silencing of the target mRNA or through degradation of the target mRNA, via complementary binding, mostly to specific sequences in the [[three prime untranslated region]] of the target gene's mRNA.<ref name="pmid22613951">{{cite journal |vauthors=Hu W, Coller J |title=What comes first: translational repression or mRNA degradation? The deepening mystery of microRNA function |journal=Cell Res. |volume=22 |issue=9 |pages=1322–4 |year=2012 |pmid=22613951 |pmc=3434348 |doi=10.1038/cr.2012.80 }}</ref>   The mechanism of translational silencing or degradation of target mRNA is implemented through the [[RNA-induced silencing complex]] (RISC).