Editing CpG site (section)

=== DNA repair genes with hyper/hypo-methylated promoters in cancers ===

DNA repair genes are frequently repressed in cancers due to hypermethylation of CpG islands within their promoters. In [[Head and neck cancer|head and neck squamous cell carcinomas]] at least 15 DNA repair genes have frequently hypermethylated promoters; these genes are ''[[XRCC1]], [[MLH3]], [[PMS1]], [[RAD51B]], [[XRCC3]], [[RAD54B]], [[BRCA1]], [[SHFM1]], [[GEN1]], [[FANCE]], [[FAAP20]], [[SPRTN]], [[SETMAR]], [[HUS1]],'' and ''[[PER1]]''.<ref name="pmid27683114">{{cite journal |vauthors=Rieke DT, Ochsenreither S, Klinghammer K, Seiwert TY, Klauschen F, Tinhofer I, Keilholz U |display-authors=6|title=Methylation of RAD51B, XRCC3 and other homologous recombination genes is associated with expression of immune checkpoints and an inflammatory signature in squamous cell carcinoma of the head and neck, lung and cervix |journal=Oncotarget |volume= 7|issue= 46|pages= 75379–75393|year=2016 |pmid=27683114 |pmc=5342748 |doi=10.18632/oncotarget.12211 }}</ref> About seventeen types of cancer are frequently deficient in one or more DNA repair genes due to hypermethylation of their promoters.<ref name="pmid22956494">{{cite book |vauthors=Jin B, Robertson KD |title=Epigenetic Alterations in Oncogenesis |chapter=DNA Methyltransferases, DNA Damage Repair, and Cancer |volume=754 |pages=3–29 |year=2013 |pmid=22956494 |pmc=3707278 |doi=10.1007/978-1-4419-9967-2_1 |series=Advances in Experimental Medicine and Biology |isbn=978-1-4419-9966-5 }}</ref> As an example, promoter hypermethylation of the DNA repair gene ''[[O-6-methylguanine-DNA methyltransferase|MGMT]]'' occurs in 93% of bladder cancers, 88% of stomach cancers, 74% of thyroid cancers, 40%-90% of colorectal cancers and 50% of brain cancers. Promoter hypermethylation of ''[[LIG4]]'' occurs in 82% of colorectal cancers. Promoter hypermethylation of ''[[NEIL1]]'' occurs in 62% of [[head and neck cancer]]s and in 42% of [[non-small-cell lung carcinoma|non-small-cell lung cancer]]s. Promoter hypermethylation of ''[[Ataxia telangiectasia mutated|ATM]]'' occurs in 47% of [[non-small-cell lung carcinoma|non-small-cell lung cancer]]s. Promoter hypermethylation of ''[[MLH1]]'' occurs in 48% of [[non-small-cell lung carcinoma|non-small-cell lung cancer]] squamous cell carcinomas. Promoter hypermethylation of ''[[FANCB]]'' occurs in 46% of [[head and neck cancer]]s.

On the other hand, the promoters of two genes, ''[[PARP1]]'' and ''[[FEN1]]'', were hypomethylated and these genes were over-expressed in numerous cancers. ''PARP1'' and ''FEN1'' are essential genes in the error-prone and mutagenic DNA repair pathway [[microhomology-mediated end joining]]. If this pathway is over-expressed the excess mutations it causes can lead to cancer. [[PARP1]] is over-expressed in tyrosine kinase-activated leukemias,<ref name="pmid25828893">{{cite journal |vauthors=Muvarak N, Kelley S, Robert C, Baer MR, Perrotti D, Gambacorti-Passerini C, Civin C, Scheibner K, Rassool FV |display-authors=6|title=c-MYC Generates Repair Errors via Increased Transcription of Alternative-NHEJ Factors, LIG3 and PARP1, in Tyrosine Kinase-Activated Leukemias |journal=Mol. Cancer Res. |volume=13 |issue=4 |pages=699–712 |year=2015 |pmid=25828893 |doi=10.1158/1541-7786.MCR-14-0422 |pmc=4398615}}</ref> in neuroblastoma,<ref name="pmid25563294">{{cite journal |vauthors=Newman EA, Lu F, Bashllari D, Wang L, Opipari AW, Castle VP |title=Alternative NHEJ Pathway Components Are Therapeutic Targets in High-Risk Neuroblastoma |journal=Mol. Cancer Res. |volume=13 |issue=3 |pages=470–82 |year=2015 |pmid=25563294 |doi=10.1158/1541-7786.MCR-14-0337 |doi-access=free }}</ref> in testicular and other germ cell tumors,<ref name="pmid23486608">{{cite journal |vauthors=Mego M, Cierna Z, Svetlovska D, Macak D, Machalekova K, Miskovska V, Chovanec M, Usakova V, Obertova J, Babal P, Mardiak J |display-authors=6|title=PARP expression in germ cell tumours |journal=J. Clin. Pathol. |volume=66 |issue=7 |pages=607–12 |year=2013 |pmid=23486608 |doi=10.1136/jclinpath-2012-201088 |s2cid=535704}}</ref> and in Ewing's sarcoma,<ref name="pmid11956622">{{cite journal |vauthors=Newman RE, Soldatenkov VA, Dritschilo A, Notario V |title=Poly(ADP-ribose) polymerase turnover alterations do not contribute to PARP overexpression in Ewing's sarcoma cells |journal=Oncol. Rep. |volume=9 |issue=3 |pages=529–32 |year=2002 |pmid=11956622 |doi= 10.3892/or.9.3.529}}</ref> [[FEN1]] is over-expressed in the majority of cancers of the breast,<ref name=Singh>{{cite journal |vauthors=Singh P, Yang M, Dai H, Yu D, Huang Q, Tan W, Kernstine KH, Lin D, Shen B |title=Overexpression and hypomethylation of flap endonuclease 1 gene in breast and other cancers |journal=Mol. Cancer Res. |volume=6 |issue=11 |pages=1710–7 |year=2008 |pmid=19010819 |pmc=2948671 |doi=10.1158/1541-7786.MCR-08-0269 }}</ref> prostate,<ref name="pmid16879693">{{cite journal |vauthors=Lam JS, Seligson DB, Yu H, Li A, Eeva M, Pantuck AJ, Zeng G, [[Steve Horvath|Horvath S]], [[Arie Belldegrun|Belldegrun AS]] |title=Flap endonuclease 1 is overexpressed in prostate cancer and is associated with a high Gleason score |journal=BJU Int. |volume=98 |issue=2 |pages=445–51 |year=2006 |pmid=16879693 |doi=10.1111/j.1464-410X.2006.06224.x |s2cid=22165252 }}</ref> stomach,<ref name="pmid15701830">{{cite journal |vauthors=Kim JM, Sohn HY, Yoon SY, Oh JH, Yang JO, Kim JH, Song KS, Rho SM, Yoo HS, Yoo HS, Kim YS, Kim JG, Kim NS |display-authors=6|title=Identification of gastric cancer-related genes using a cDNA microarray containing novel expressed sequence tags expressed in gastric cancer cells |journal=Clin. Cancer Res. |volume=11 |issue=2 Pt 1 |pages=473–82 |year=2005 |doi=10.1158/1078-0432.473.11.2|pmid=15701830 |doi-access=free }}</ref><ref name="pmid24590400">{{cite journal |vauthors=Wang K, Xie C, Chen D |title=Flap endonuclease 1 is a promising candidate biomarker in gastric cancer and is involved in cell proliferation and apoptosis |journal=Int. J. Mol. Med. |volume=33 |issue=5 |pages=1268–74 |year=2014 |pmid=24590400 |doi=10.3892/ijmm.2014.1682 |doi-access=free }}</ref> neuroblastomas,<ref name="pmid15922863">{{cite journal |vauthors=Krause A, Combaret V, Iacono I, Lacroix B, Compagnon C, Bergeron C, Valsesia-Wittmann S, Leissner P, Mougin B, Puisieux A |display-authors=6|title=Genome-wide analysis of gene expression in neuroblastomas detected by mass screening |journal=Cancer Lett. |volume=225 |issue=1 |pages=111–20 |year=2005 |pmid=15922863 |doi=10.1016/j.canlet.2004.10.035 |s2cid=44644467|url=http://hal.archives-ouvertes.fr/docs/00/15/79/17/PDF/Cancer_Letters_2004.pdf}}</ref> pancreatic,<ref name="pmid12651607">{{cite journal |vauthors=Iacobuzio-Donahue CA, Maitra A, Olsen M, Lowe AW, van Heek NT, Rosty C, Walter K, Sato N, Parker A, Ashfaq R, Jaffee E, Ryu B, Jones J, Eshleman JR, Yeo CJ, Cameron JL, Kern SE, Hruban RH, Brown PO, Goggins M |display-authors=6|title=Exploration of global gene expression patterns in pancreatic adenocarcinoma using cDNA microarrays |journal=Am. J. Pathol. |volume=162 |issue=4 |pages=1151–62 |year=2003 |pmid=12651607 |pmc=1851213 |doi=10.1016/S0002-9440(10)63911-9 }}</ref> and lung.<ref name="pmid19596913">{{cite journal |vauthors=Nikolova T, Christmann M, Kaina B |title=FEN1 is overexpressed in testis, lung and brain tumors |journal=Anticancer Res. |volume=29 |issue=7 |pages=2453–9 |year=2009 |pmid=19596913 }}</ref>

DNA damage appears to be the primary underlying cause of cancer.<ref name="pmid18403632">{{cite journal |vauthors=[[Michael B. Kastan|Kastan MB]] |title=DNA damage responses: mechanisms and roles in human disease: 2007 G.H.A. Clowes Memorial Award Lecture |journal=Mol. Cancer Res. |volume=6 |issue=4 |pages=517–24 |year=2008 |pmid=18403632 |doi=10.1158/1541-7786.MCR-08-0020 |doi-access=free }}</ref><ref name=BernsteinPrasad>{{cite book |last1= Bernstein |first1=C |last2=Prasad |first2=AR |last3=Nfonsam |first3=V |last4=Bernstein |first4=H. |year=2013 |chapter= Chapter 16: DNA Damage, DNA Repair and Cancer |title= New Research Directions in DNA Repair |editor-first=Clark |editor-last=Chen |isbn=978-953-51-1114-6|page=413|publisher=BoD – Books on Demand }}</ref> If accurate DNA repair is deficient, DNA damages tend to accumulate. Such excess DNA damage can increase [[mutation]]al errors during [[DNA replication]] due to error-prone [[DNA repair#Translesion synthesis|translesion synthesis]]. Excess DNA damage can also increase [[Epigenetics|epigenetic]] alterations due to errors during DNA repair.<ref name=Hagan>{{cite journal |vauthors=O'Hagan HM, Mohammad HP, Baylin SB |title=Double strand breaks can initiate gene silencing and SIRT1-dependent onset of DNA methylation in an exogenous promoter CpG island |journal=PLOS Genetics |volume=4 |issue=8 |pages=e1000155 |year=2008 |pmid=18704159 |pmc=2491723 |doi=10.1371/journal.pgen.1000155 |doi-access=free }}</ref><ref name=Cuozzo>{{cite journal |vauthors=Cuozzo C, Porcellini A, Angrisano T |title=DNA damage, homology-directed repair, and DNA methylation |journal=PLOS Genetics |volume=3 |issue=7 |pages=e110 | date=July 2007 |pmid=17616978 |pmc=1913100 |doi=10.1371/journal.pgen.0030110|display-authors=etal |doi-access=free }}</ref> Such mutations and epigenetic alterations can give rise to [[cancer]] (see [[Neoplasm#Malignant neoplasms|malignant neoplasms]]). Thus, CpG island hyper/hypo-methylation in the promoters of DNA repair genes are likely central to progression to cancer.