Colorectal carcinogenesis (CRC) is caused by the gradual long-term accumulation of both genetic and epigenetic changes. Recently, epigenetic alterations have been included in the classification of the CRC molecular subtype, and this points out their prognostic impact. As epigenetic modifications are reversible, they may represent relevant therapeutic targets. DNA methylation, catalyzed by DNA methyltransferases (DNMTs), regulates gene expression. For many years, the deregulation of DNA methylation has been considered to play a substantial part in CRC etiology and evolution. Despite considerable advances in CRC treatment, patient therapy response persists as limited, and their profit from systemic therapies are often hampered by the introduction of chemoresistance. In addition, inter-individual changes in therapy response in CRC patients can arise from their specific (epi)genetic compositions. In this review article, we summarize the options of CRC treatment based on DNA methylation status for their predictive value. This review also includes the therapy outcomes based on the patient's methylation status in CRC patients. In addition, the current challenge of research is to develop therapeutic inhibitors of DNMT. Based on the essential role of DNA methylation in CRC development, the application of DNMT inhibitors was recently proposed for the treatment of CRC patients, especially in patients with DNA hypermethylation.

Biomedical Centre Faculty of Medicine in Pilsen Charles University Alej Svobody 76 323 00 Pilsen Czech Republic

Department of Molecular Biology of Cancer Institute of Experimental Medicine Videnska 1083 14 200 Prague Czech Republic

Department of Oncology 1st Faculty of Medicine Charles University and Thomayer Hospital Videnska 800 140 59 Prague Czech Republic

Institute of Biology and Medical Genetics 1st Faculty of Medicine Charles University Albertov 4 128 00 Prague Czech Republic

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Lazennec G., Lam P.Y. Recent discoveries concerning the tumor-mesenchymal stem cell interactions. Biochim. Biophys. Acta Rev. Cancer. 2016;1866:290–299. doi: 10.1016/j.bbcan.2016.10.004. PubMed DOI

El Bairi K., Tariq K., Himri I., Jaafari A., Smaili W., Kandhro A.H., Gouri A., Ghazi B. Decoding colorectal cancer epigenomics. Cancer Genet. 2018;220:49–76. doi: 10.1016/j.cancergen.2017.11.001. PubMed DOI

Farkas S., Vymetalkova V., Vodickova L., Vodicka P., Nilsson T.K. DNA methylation changes in genes frequently mutated in sporadic colorectal cancer and in the DNA repair and Wnt/β-catenin signaling pathway genes. Epigenomics. 2014;6:179–191. doi: 10.2217/epi.14.7. PubMed DOI

Vymetalkova V., Vodicka P., Pardini B., Rosa F., Levy M., Schneiderova M., Liska V., Vodickova L., Nilsson T.K., Farkas S. Epigenome-wide analysis of DNA methylation reveals a rectal cancer-specific epigenomic signature. Epigenomics. 2016;8:1193–1207. doi: 10.2217/epi-2016-0044. PubMed DOI

Vymetalkova V., Vodicka P., Vodenkova S., Alonso S., Schneider-Stock R. DNA methylation and chromatin modifiers in colorectal cancer. Mol. Asp. Med. 2019;69:73–92. doi: 10.1016/j.mam.2019.04.002. PubMed DOI

Ehrlich M., Gama-Sosa M.A., Huang L.-H., Midgett R.M., Kuo K.C., McCune R.A., Gehrke C. Amount and distribution of 5-methylcytosine in human DNA from different types of tissues or cells. Nucleic Acids Res. 1982;10:2709–2721. doi: 10.1093/nar/10.8.2709. PubMed DOI PMC

Jones P.A. Functions of DNA methylation: Islands, start sites, gene bodies and beyond. Nat. Rev. Genet. 2012;13:484–492. doi: 10.1038/nrg3230. PubMed DOI

Fraga M.F., Esteller M. Epigenetics and aging: The targets and the marks. Trends Genet. 2007;23:413–418. doi: 10.1016/j.tig.2007.05.008. PubMed DOI

Takeshima H., Ushijima T. Accumulation of genetic and epigenetic alterations in normal cells and cancer risk. NPJ Precis. Oncol. 2019;3 doi: 10.1038/s41698-019-0079-0. PubMed DOI PMC

Mathers J.C., Strathdee G., Relton C.L. Induction of Epigenetic Alterations by Dietary and Other Environmental Factors. Adv. Genet. 2010;71:3–39. doi: 10.1016/b978-0-12-380864-6.00001-8. PubMed DOI

Issa J.-P., Ottaviano Y.L., Celano P., Hamilton S.R., Davidson N.E., Baylin S.B. Methylation of the oestrogen receptor CpG island links ageing and neoplasia in human colon. Nat. Genet. 1994;7:536–540. doi: 10.1038/ng0894-536. PubMed DOI

Issa J.-P., Ahuja N., Toyota M., Bronner M.P., A Brentnall T. Accelerated age-related CpG island methylation in ulcerative colitis. Cancer Res. 2001;61:3573–3577. PubMed

Niwa T., Tsukamoto T., Toyoda T., Mori A., Tanaka H., Maekita T., Ichinose M., Tatematsu M., Ushijima T. Inflammatory Processes Triggered by Helicobacter pylori Infection Cause Aberrant DNA Methylation in Gastric Epithelial Cells. Cancer Res. 2010;70:1430–1440. doi: 10.1158/0008-5472.CAN-09-2755. PubMed DOI

Nishida N., Nagasaka T., Nishimura T., Ikai I., Boland C.R., Goel A. Aberrant methylation of multiple tumor suppressor genes in aging liver, chronic hepatitis, and hepatocellular carcinoma. Hepatology. 2008;47:908–918. doi: 10.1002/hep.22110. PubMed DOI PMC

Gonzalez-Jaramillo V., Portilla-Fernandez E., Glisic M., Voortman T., Ghanbari M., Bramer W., Chowdhury R., Nijsten T., Dehghan A., Franco O.H., et al. Epigenetics and Inflammatory Markers: A Systematic Review of the Current Evidence. Int. J. Inflamm. 2019;2019:6273680. doi: 10.1155/2019/6273680. PubMed DOI PMC

Oka D., Yamashita S., Tomioka T., Nakanishi Y., Kato H., Kaminishi M., Ushijima T. The presence of aberrant DNA methylation in noncancerous esophageal mucosae in association with smoking history. Cancer. 2009;115:3412–3426. doi: 10.1002/cncr.24394. PubMed DOI

Cheng A., Culhane A.C., Chan M.W.Y., Venkataramu C.R., Ehrich M., Nasir A., Rodriguez B.A., Liu J., Yan P.S., Quackenbush J., et al. Epithelial progeny of estrogen-exposed breast progenitor cells display a cancer-like methylome. Cancer Res. 2008;68:1786–1796. doi: 10.1158/0008-5472.CAN-07-5547. PubMed DOI PMC

Choi S.-W., Corrocher R., Friso S. Nutrition and Epigenetics. 1st ed. CRC Press; Boca Raton, FL, USA: 2009. Nutrients and DNA methylation; pp. 106–125.

Reed M.C., Nijhout H.F., Neuhouser M.L., Gregory J.F., Shane B., James S.J., Boynton A., Ulrich C.M. A Mathematical Model Gives Insights into Nutritional and Genetic Aspects of Folate-Mediated One-Carbon Metabolism. J. Nutr. 2006;136:2653–2661. doi: 10.1093/jn/136.10.2653. PubMed DOI

Kadayifci F.Z., Zheng S., Pan Y.-X. Molecular Mechanisms Underlying the Link between Diet and DNA Methylation. Int. J. Mol. Sci. 2018;19:4055. doi: 10.3390/ijms19124055. PubMed DOI PMC

Mazin A.L. Suicidal function of DNA methylation in age-related genome disintegration. Ageing Res. Rev. 2009;8:314–327. doi: 10.1016/j.arr.2009.04.005. PubMed DOI

Johnson A.A., Akman K., Calimport S., Wuttke D., Stolzing A., De Magalhães J.P. The Role of DNA Methylation in Aging, Rejuvenation, and Age-Related Disease. Rejuvenation Res. 2012;15:483–494. doi: 10.1089/rej.2012.1324. PubMed DOI PMC

Jones M.J., Goodman S.J., Kobor M.S. DNA methylation and healthy human aging. Aging Cell. 2015;14:924–932. doi: 10.1111/acel.12349. PubMed DOI PMC

Horvath S., Zhang Y., Langfelder P., Kahn R.S., Boks M.P.M., Van Eijk K., Berg L.H.V.D., Ophoff R.A. Aging effects on DNA methylation modules in human brain and blood tissue. Genome Boil. 2012;13:R97. doi: 10.1186/gb-2012-13-10-r97. PubMed DOI PMC

Fraga M.F., Ballestar E., Paz M.F., Ropero S., Setien F., Ballestar M.L., Heine-Suñer D., Cigudosa J.C., Urioste M., Benitez J., et al. Epigenetic differences arise during the lifetime of monozygotic twins. Proc. Natl. Acad. Sci. USA. 2005;102:10604–10609. doi: 10.1073/pnas.0500398102. PubMed DOI PMC

Jung M., Pfeifer G.P. Aging and DNA methylation. BMC Biol. 2015;13:7. doi: 10.1186/s12915-015-0118-4. PubMed DOI PMC

Li Y., Deuring J., Peppelenbosch M.P., Kuipers E.J., De Haar C., Van Der Woude C.J. IL-6-induced DNMT1 activity mediates SOCS3 promoter hypermethylation in ulcerative colitis-related colorectal cancer. Carcinogenesis. 2012;33:1889–1896. doi: 10.1093/carcin/bgs214. PubMed DOI

Lee J.-H., Kang M.-J., Han H.-Y., Lee M.-G., Jeong S.-I., Ryu B.-K., Ha T.-K., Her N.-G., Han J., Park S.J., et al. Epigenetic Alteration of PRKCDBP in Colorectal Cancers and Its Implication in Tumor Cell Resistance to TNF-Induced Apoptosis. Clin. Cancer Res. 2011;17:7551–7562. doi: 10.1158/1078-0432.CCR-11-1026. PubMed DOI

Patel S.A.A., Bhambra U., Charalambous M.P., David R.M., Edwards R.J., Lightfoot T., Boobis A.R., Gooderham N.J. Interleukin-6 mediated upregulation of CYP1B1 and CYP2E1 in colorectal cancer involves DNA methylation, miR27b and STAT3. Br. J. Cancer. 2014;111:2287–2296. doi: 10.1038/bjc.2014.540. PubMed DOI PMC

Rubino M., Kunderfranco P., Basso G., Greco C.M., Pasqualini F., Serio S., Roncalli M., Laghi L., Mantovani A., Papait R., et al. Epigenetic regulation of the extrinsic oncosuppressor PTX3 gene in inflammation and cancer. Oncoimmunology. 2017;6:e1333215. doi: 10.1080/2162402X.2017.1333215. PubMed DOI PMC

I Selmin O., Fang C., Lyon A.M., Doetschman T.C., A Thompson P., Martinez J.D., Smith J.W., Lance P.M., Romagnolo D.F. Inactivation of Adenomatous Polyposis Coli Reduces Bile Acid/Farnesoid X Receptor Expression through Fxr gene CpG Methylation in Mouse Colon Tumors and Human Colon Cancer Cells. J. Nutr. 2015;146:236–242. doi: 10.3945/jn.115.216580. PubMed DOI PMC

Castellano-Castillo D., Morcillo S., Clemente-Postigo M., Crujeiras A.B., Fernández-García J.C., Torres E., Tinahones F.J., Macías-González M. Adipose tissue inflammation and VDR expression and methylation in colorectal cancer. Clin. Epigenetics. 2018;10:60. doi: 10.1186/s13148-018-0493-0. PubMed DOI PMC

Yang Z.-H., Dang Y.-Q., Ji G. Role of epigenetics in transformation of inflammation into colorectal cancer. World J. Gastroenterol. 2019;25:2863–2877. doi: 10.3748/wjg.v25.i23.2863. PubMed DOI PMC

West N., McCuaig S., Franchini F., Powrie F.M. Emerging cytokine networks in colorectal cancer. Nat. Rev. Immunol. 2015;15:615–629. doi: 10.1038/nri3896. PubMed DOI

Foran E., Garrity-Park M.M., Mureau C., Newell J., Smyrk T.C., Limburg P.J., Egan L.J. Upregulation of DNA methyltransferase-mediated gene silencing, anchorage-independent growth, and migration of colon cancer cells by interleukin-6. Mol. Cancer Res. 2010;8:471–481. doi: 10.1158/1541-7786.MCR-09-0496. PubMed DOI

Gerecke C., Scholtka B., Löwenstein Y., Fait I., Gottschalk U., Rogoll D., Melcher R., Kleuser B. Hypermethylation of ITGA4, TFPI2 and VIMENTIN promoters is increased in inflamed colon tissue: Putative risk markers for colitis-associated cancer. J. Cancer Res. Clin. Oncol. 2015;141:2097–2107. doi: 10.1007/s00432-015-1972-8. PubMed DOI

A Jones P. The DNA methylation paradox. Trends Genet. 1999;15:34–37. doi: 10.1016/S0168-9525(98)01636-9. PubMed DOI

Vaiserman A.M. Epigenetics of Aging and Longevity. 1st ed. Academic Press; London, UK: 2017.

Rideout W., Coetzee G., Olumi A., Jones P. 5-Methylcytosine as an endogenous mutagen in the human LDL receptor and p53 genes. Science. 1990;249:1288–1290. doi: 10.1126/science.1697983. PubMed DOI

Cooper D.N., Youssoufian H. The CpG dinucleotide and human genetic disease. Qual. Life Res. 1988;78:151–155. doi: 10.1007/BF00278187. PubMed DOI

Laurent L., Wong E., Li G., Huynh T., Tsirigos A., Ong C.T., Low H.M., Sung W.-K., Rigoutsos I., Loring J.F., et al. Dynamic changes in the human methylome during differentiation. Genome Res. 2010;20:320–331. doi: 10.1101/gr.101907.109. PubMed DOI PMC

Maunakea A.K., Chepelev I., Cui K., Zhao K. Intragenic DNA methylation modulates alternative splicing by recruiting MeCP2 to promote exon recognition. Cell Res. 2013;23:1256–1269. doi: 10.1038/cr.2013.110. PubMed DOI PMC

Schwartz S., Meshorer E., Ast G. Chromatin organization marks exon-intron structure. Nat. Struct. Mol. Boil. 2009;16:990–995. doi: 10.1038/nsmb.1659. PubMed DOI

Chodavarapu R.K., Feng S., Bernatavichute Y.V., Chen P.-Y., Stroud H., Yu Y., Hetzel J.A., Kuo F., Kim J., Cokus S.J., et al. Relationship between nucleosome positioning and DNA methylation. Nature. 2010;466:388–392. doi: 10.1038/nature09147. PubMed DOI PMC

Moarefi A.H., Chédin F. ICF Syndrome Mutations Cause a Broad Spectrum of Biochemical Defects in DNMT3B-Mediated De Novo DNA Methylation. J. Mol. Boil. 2011;409:758–772. doi: 10.1016/j.jmb.2011.04.050. PubMed DOI

Scelfo A., Fachinetti D. Keeping the Centromere under Control: A Promising Role for DNA Methylation. Cells. 2019;8:912. doi: 10.3390/cells8080912. PubMed DOI PMC

Hashimshony T., Zhang J., Keshet I., Bustin M., Cedar H. The role of DNA methylation in setting up chromatin structure during development. Nat. Genet. 2003;34:187–192. doi: 10.1038/ng1158. PubMed DOI

Kass S.U., Landsberger N., Wolffe A.P. DNA methylation directs a time-dependent repression of transcription initiation. Curr. Boil. 1997;7:157–165. doi: 10.1016/S0960-9822(97)70086-1. PubMed DOI

Venolia L., Gartler S.M. Comparison of transformation efficiency of human active and inactive X-chromosomal DNA. Nature. 1983;302:82–83. doi: 10.1038/302082a0. PubMed DOI

Landry J.-R., Mager D.L., Wilhelm B.T. Complex controls: The role of alternative promoters in mammalian genomes. Trends Genet. 2003;19:640–648. doi: 10.1016/j.tig.2003.09.014. PubMed DOI

Maunakea A.K., Nagarajan R.P., Bilenky M., Ballinger T.J., D’Souza C., Fouse S.D., Johnson B.E., Hong C., Nielsen C., Zhao Y., et al. Conserved role of intragenic DNA methylation in regulating alternative promoters. Nature. 2010;466:253–257. doi: 10.1038/nature09165. PubMed DOI PMC

Gal-Yam E.N., Egger G., Iniguez L., Holster H., Einarsson S., Zhang X., Lin J.C., Liang G., Jones P.A., Tanay A. Frequent switching of Polycomb repressive marks and DNA hypermethylation in the PC3 prostate cancer cell line. Proc. Natl. Acad. Sci. USA. 2008;105:12979–12984. doi: 10.1073/pnas.0806437105. PubMed DOI PMC

Ohm J.E., McGarvey K.M., Yu X., Cheng L., Schuebel K.E., Cope L., Mohammad H.P., Chen W., Daniel V.C., Yu W., et al. A stem cell–like chromatin pattern may predispose tumor suppressor genes to DNA hypermethylation and heritable silencing. Nat. Genet. 2007;39:237–242. doi: 10.1038/ng1972. PubMed DOI PMC

Schlesinger Y., Straussman R., Keshet I., Farkash S., Hecht M., Zimmerman J., Eden E., Yakhini Z., Ben-Shushan E., Reubinoff B., et al. Polycomb-mediated methylation on Lys27 of histone H3 pre-marks genes for de novo methylation in cancer. Nat. Genet. 2006;39:232–236. doi: 10.1038/ng1950. PubMed DOI

Widschwendter M., Fiegl H., Egle D., Mueller-Holzner E., Spizzo G., Marth C., Weisenberger D.J., Campan M., Young J., Jacobs I., et al. Epigenetic stem cell signature in cancer. Nat. Genet. 2006;39:157–158. doi: 10.1038/ng1941. PubMed DOI

Golbabapour S., Majid N.A., Hassandarvish P., Hajrezaie M., Abdulla M.A., Hadi A.H.A. Gene Silencing and Polycomb Group Proteins: An Overview of their Structure, Mechanisms and Phylogenetics. OMICS: A J. Integr. Boil. 2013;17:283–296. doi: 10.1089/omi.2012.0105. PubMed DOI PMC

Dietrich N., Bracken A.P., Trinh E., Schjerling C.K., Koseki H., Rappsilber J., Helin K., Hansen K. Bypass of senescence by the polycomb group protein CBX8 through direct binding to the INK4A-ARF locus. EMBO J. 2007;26:1637–1648. doi: 10.1038/sj.emboj.7601632. PubMed DOI PMC

Vissers J.H.A., Van Lohuizen M., Citterio E. The emerging role of Polycomb repressors in the response to DNA damage. J. Cell Sci. 2012;125:3939–3948. doi: 10.1242/jcs.107375. PubMed DOI

Francis N.J. Chromatin Compaction by a Polycomb Group Protein Complex. Science. 2004;306:1574–1577. doi: 10.1126/science.1100576. PubMed DOI

Irizarry R.A., Ladd-Acosta C., Wen B., Wu Z., Montano C., Onyango P., Cui H., Gabo K., Rongione M., Webster M., et al. The human colon cancer methylome shows similar hypo- and hypermethylation at conserved tissue-specific CpG island shores. Nat. Genet. 2009;41:178–186. doi: 10.1038/ng.298. PubMed DOI PMC

Ogoshi K., Hashimoto S.-I., Nakatani Y., Qu W., Oshima K., Tokunaga K., Sugano S., Hattori M., Morishita S., Matsushima K. Genome-wide profiling of DNA methylation in human cancer cells. Genomics. 2011;98:280–287. doi: 10.1016/j.ygeno.2011.07.003. PubMed DOI

Johnson K.C., Houseman E.A., King J.E., Von Herrmann K.M., Fadul C.E., Christensen B.C. 5-Hydroxymethylcytosine localizes to enhancer elements and is associated with survival in glioblastoma patients. Nat. Commun. 2016;7:13177. doi: 10.1038/ncomms13177. PubMed DOI PMC

Spainhour J.C., Lim H.S., Yi S.V., Qiu P. Correlation Patterns Between DNA Methylation and Gene Expression in The Cancer Genome Atlas. Cancer Inform. 2019;18:1176935119828776. doi: 10.1177/1176935119828776. PubMed DOI PMC

Goll M.G., Kirpekar F., Maggert K.A., Yoder J.A., Hsieh C.-L., Zhang X., Golic K.G., Jacobsen S.E., Bestor T.H. Methylation of tRNAAsp by the DNA Methyltransferase Homolog Dnmt2. Science. 2006;311:395–398. doi: 10.1126/science.1120976. PubMed DOI

Smith Z.D., Meissner A. DNA methylation: Roles in mammalian development. Nat. Rev. Genet. 2013;14:204–220. doi: 10.1038/nrg3354. PubMed DOI

Cheng X., Blumenthal R. Mammalian DNA Methyltransferases: A Structural Perspective. Structure. 2008;16:341–350. doi: 10.1016/j.str.2008.01.004. PubMed DOI PMC

Poh W.J., Wee C.P.P., Gao Z. DNA Methyltransferase Activity Assays: Advances and Challenges. Theranostics. 2016;6:369–391. doi: 10.7150/thno.13438. PubMed DOI PMC

Zhang W., Xu J. DNA methyltransferases and their roles in tumorigenesis. Biomark. Res. 2017;5:1. doi: 10.1186/s40364-017-0081-z. PubMed DOI PMC

Nan X., Ng H.H., Johnson C.A., Laherty C.D., Turner B.M., Eisenman R.N., Bird A. Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex. Nature. 1998;393:386–389. doi: 10.1038/30764. PubMed DOI

Privalsky M.L. Transcriptional Corepressors: Mediators of Eukaryotic Gene Repression. Springer; Heidelberg, Germany: 2013.

Mahmood N., Rabbani S.A. DNA Methylation Readers and Cancer: Mechanistic and Therapeutic Applications. Front. Oncol. 2019;9:489. doi: 10.3389/fonc.2019.00489. PubMed DOI PMC

Buck-Koehntop B.A., Defossez P.-A. On how mammalian transcription factors recognize methylated DNA. Epigenetics. 2013;8:131–137. doi: 10.4161/epi.23632. PubMed DOI PMC

Guo J.U., Su Y., Zhong C., Ming G.-L., Song H. Hydroxylation of 5-Methylcytosine by TET1 Promotes Active DNA Demethylation in the Adult Brain. Cell. 2011;145:423–434. doi: 10.1016/j.cell.2011.03.022. PubMed DOI PMC

Qin W., Leonhardt H., Pichler G. Regulation of DNA methyltransferase 1 by interactions and modifications. Nucleus. 2011;2:392–402. doi: 10.4161/nucl.2.5.17928. PubMed DOI

Edwards J.R., Yarychkivska O., Boulard M., Bestor T.H. DNA methylation and DNA methyltransferases. Epigenetics Chromatin. 2017;10:23. doi: 10.1186/s13072-017-0130-8. PubMed DOI PMC

Lee B., Muller M.T. SUMOylation enhances DNA methyltransferase 1 activity. Biochem. J. 2009;421:449–461. doi: 10.1042/BJ20090142. PubMed DOI

Ghoshal K., Datta J., Majumder S., Bai S., Kutay H., Motiwala T., Jacob S.T. 5-Aza-Deoxycytidine Induces Selective Degradation of DNA Methyltransferase 1 by a Proteasomal Pathway That Requires the KEN Box, Bromo-Adjacent Homology Domain, and Nuclear Localization Signal. Mol. Cell. Boil. 2005;25:4727–4741. doi: 10.1128/MCB.25.11.4727-4741.2005. PubMed DOI PMC

Deshaies R.J. SCF and Cullin/RING H2-Based Ubiquitin Ligases. Annu. Rev. Cell Dev. Boil. 1999;15:435–467. doi: 10.1146/annurev.cellbio.15.1.435. PubMed DOI

Naumann M., Bech-Otschir D., Huang X., Ferrell K., Dubiel W. COP9 Signalosome-directed c-Jun Activation/Stabilization Is Independent of JNK. J. Boil. Chem. 1999;274:35297–35300. doi: 10.1074/jbc.274.50.35297. PubMed DOI

Viré E., Brenner C., Deplus R., Blanchon L., Fraga M., Mirjolet C., Morey L., Van Eynde A., Bernard D., Vanderwinden J.-M., et al. The Polycomb group protein EZH2 directly controls DNA methylation. Nature. 2005;439:871–874. doi: 10.1038/nature04431. PubMed DOI

Linhart H.G., Lin H., Yamada Y., Moran E., Steine E.J., Gokhale S., Lo G., Cantu E., Ehrich M., He T., et al. Dnmt3b promotes tumorigenesis in vivo by gene-specific de novo methylation and transcriptional silencing. Genome Res. 2007;21:3110–3122. doi: 10.1101/gad.1594007. PubMed DOI PMC

Ibrahim A.E.K., Arends M.J., Silva A.-L., Wyllie A.H., Greger L., Ito Y., Vowler S.L., Huang T.H.-M., Murrell A., Brenton J.D., et al. Sequential DNA methylation changes are associated with DNMT3B overexpression in colorectal neoplastic progression. Gut. 2010;60:499–508. doi: 10.1136/gut.2010.223602. PubMed DOI

Nosho K., Shima K., Irahara N., Kure S., Baba Y., Kirkner G.J., Chen L., Gokhale S., Hazra A., Spiegelman N., et al. DNMT3B expression might contribute to CpG island methylator phenotype in colorectal cancer. Clin. Cancer Res. 2009;15:3663–3671. doi: 10.1158/1078-0432.CCR-08-2383. PubMed DOI PMC

Kanai Y., Ushijima S., Nakanishi Y., Sakamoto M., Hirohashi S. Mutation of the DNA methyltransferase (DNMT) 1 gene in human colorectal cancers. Cancer Lett. 2003;192:75–82. doi: 10.1016/S0304-3835(02)00689-4. PubMed DOI

Bernal C., Vargas M., Ossandón F., Santibáñez E., Urrutia J., Luengo V., Zavala L.F., Backhouse C., Palma M., Argandoña J., et al. DNA methylation profile in diffuse type gastric cancer: Evidence for hypermethylation of the BRCA1 promoter region in early-onset gastric carcinogenesis. Boil. Res. 2009;41:303–315. doi: 10.4067/S0716-97602008000300007. PubMed DOI

Sharma S., Kelly T.K., Jones P.A. Epigenetics in cancer. Carcinog. 2009;31:27–36. doi: 10.1093/carcin/bgp220. PubMed DOI PMC

Ying J., Li H., Seng T.J., Langford C., Srivastava G., Tsao S.W., Putti T., Murray P., Chan A., Tao Q. Functional epigenetics identifies a protocadherin PCDH10 as a candidate tumor suppressor for nasopharyngeal, esophageal and multiple other carcinomas with frequent methylation. Oncogene. 2005;25:1070–1080. doi: 10.1038/sj.onc.1209154. PubMed DOI

Chan T.L., Yuen S.T., Kong C.K., Chan Y.W., Chan A.S., Ng W.F., Tsui W.Y., Lo M.W., Tam W.Y., Li V.S.W., et al. Heritable germline epimutation of MSH2 in a family with hereditary nonpolyposis colorectal cancer. Nat. Genet. 2006;38:1178–1183. doi: 10.1038/ng1866. PubMed DOI

Yang X., Lay F., Han H., Jones P.A. Targeting DNA methylation for epigenetic therapy. Trends Pharmacol. Sci. 2010;31:536–546. doi: 10.1016/j.tips.2010.08.001. PubMed DOI PMC

Bariol C., Suter C., Cheong K., Ku S.-L., Meagher A., Hawkins N., Ward R. The Relationship between Hypomethylation and CpG Island Methylation in Colorectal Neoplasia. Am. J. Pathol. 2003;162:1361–1371. doi: 10.1016/S0002-9440(10)63932-6. PubMed DOI PMC

Ehrlich M. The Controversial Denouement of Vertebrate DNA Methylation Research. Biochemistry. 2005;70:568–575. doi: 10.1007/s10541-005-0150-z. PubMed DOI

Frigola J., Sole X., Paz M.F., Moreno V., Esteller M., Capellá G., Peinado M.A. Differential DNA hypermethylation and hypomethylation signatures in colorectal cancer. Hum. Mol. Genet. 2004;14:319–326. doi: 10.1093/hmg/ddi028. PubMed DOI

Plava J., Cihova M., Burikova M., Matuskova M., Kucerova L., Miklikova S. Recent advances in understanding tumor stroma-mediated chemoresistance in breast cancer. Mol. Cancer. 2019;18:67. doi: 10.1186/s12943-019-0960-z. PubMed DOI PMC

Xing F. Cancer associated fibroblasts (CAFs) in tumor microenvironment. Front. Biosci. 2010;15:166. doi: 10.2741/3613. PubMed DOI PMC

Du H., Che G. Genetic alterations and epigenetic alterations of cancer-associated fibroblasts. Oncol. Lett. 2016;13:3–12. doi: 10.3892/ol.2016.5451. PubMed DOI PMC

Karagiannis G.S., Poutahidis T., Erdman S.E., Kirsch R., Riddell R.H., Diamandis E. Cancer-associated fibroblasts drive the progression of metastasis through both paracrine and mechanical pressure on cancer tissue. Mol. Cancer Res. 2012;10:1403–1418. doi: 10.1158/1541-7786.MCR-12-0307. PubMed DOI PMC

Gascard P., Tlsty T.D. Carcinoma-associated fibroblasts: Orchestrating the composition of malignancy. Genome Res. 2016;30:1002–1019. doi: 10.1101/gad.279737.116. PubMed DOI PMC

Ishii G., Ochiai A., Neri S. Phenotypic and functional heterogeneity of cancer-associated fibroblast within the tumor microenvironment. Adv. Drug Deliv. Rev. 2016;99:186–196. doi: 10.1016/j.addr.2015.07.007. PubMed DOI

Son G.M., Kwon M.-S., Shin D.-H., Shin N., Ryu D., Kang C.-D. Comparisons of cancer-associated fibroblasts in the intratumoral stroma and invasive front in colorectal cancer. Medicine. 2019;98:e15164. doi: 10.1097/MD.0000000000015164. PubMed DOI PMC

Fiori M.E., Di Franco S., Villanova L., Bianca P., Stassi G., De Maria R. Cancer-associated fibroblasts as abettors of tumor progression at the crossroads of EMT and therapy resistance. Mol. Cancer. 2019;18:70. doi: 10.1186/s12943-019-0994-2. PubMed DOI PMC

Banerjee J., Mishra R., Li X., Jackson R.S., Sharma A., Bhowmick N.A. A reciprocal role of prostate cancer on stromal DNA damage. Oncogene. 2013;33:4924–4931. doi: 10.1038/onc.2013.431. PubMed DOI PMC

Adany R., Heimer R., Caterson B., Sorrell J.M., Iozzo R.V. Altered expression of chondroitin sulfate proteoglycan in the stroma of human colon carcinoma. Hypomethylation of PG-40 gene correlates with increased PG-40 content and mRNA levels. J. Boil. Chem. 1990;265:11389–11396. PubMed

Matsunoki A., Kawakami K., Kotake M., Kaneko M., Kitamura H., Ooi A., Watanabe G., Minamoto T. LINE-1 methylation shows little intra-patient heterogeneity in primary and synchronous metastatic colorectal cancer. BMC Cancer. 2012;12:574. doi: 10.1186/1471-2407-12-574. PubMed DOI PMC

Toyota M., Ahuja N., Suzuki H., Itoh F., Imai K., Baylin S.B., Issa J.P. Aberrant methylation in gastric cancer associated with the CpG island methylator phenotype. Cancer Res. 1999;59:5438–5442. PubMed

Weisenberger D.J., Siegmund K., Campan M., Young J., I Long T., Faasse M., Kang G.H., Widschwendter M., Weener D., Buchanan D., et al. CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer. Nat. Genet. 2006;38:787–793. doi: 10.1038/ng1834. PubMed DOI

McGivern A., Wynter C., Whitehall V., Kambara T., Spring K.J., Walsh M., Barker M., Arnold S., Simms L., Leggett B., et al. Promoter Hypermethylation Frequency and BRAF Mutations Distinguish Hereditary Non-Polyposis Colon Cancer from Sporadic MSI-H Colon Cancer. Fam. Cancer. 2002;3:101–107. doi: 10.1023/B:FAME.0000039861.30651.c8. PubMed DOI

Hawkins N., Norrie M., Cheong K., Mokany E., Ku S.-L., Meagher A., O’Connor T., Ward R. CpG island methylation in sporadic colorectal cancers and its relationship to microsatellite instability. Gastroenterology. 2002;122:1376–1387. doi: 10.1053/gast.2002.32997. PubMed DOI

Van Rijnsoever M., Grieu F., Elsaleh H., Joseph D., Iacopetta B. Characterisation of colorectal cancers showing hypermethylation at multiple CpG islands. Gut. 2002;51:797–802. doi: 10.1136/gut.51.6.797. PubMed DOI PMC

Slattery M.L., Curtin K., Wolff R.K., Boucher K.M., Sweeney C., Edwards S., Caan B.J., Samowitz W. A Comparison of Colon and Rectal Somatic DNA Alterations. Dis. Colon Rectum. 2009;52:1304–1311. doi: 10.1007/DCR.0b013e3181a0e5df. PubMed DOI PMC

Barault L., Charon-Barra C., Jooste V., De La Vega M.F., Martin L., Roignot P., Rat P., Bouvier A.-M., Laurent-Puig P., Faivre J., et al. Hypermethylator Phenotype in Sporadic Colon Cancer: Study on a Population-Based Series of 582 Cases. Cancer Res. 2008;68:8541–8546. doi: 10.1158/0008-5472.CAN-08-1171. PubMed DOI

Nosho K., Irahara N., Shima K., Kure S., Kirkner G.J., Schernhammer E., Hazra A., Hunter D.J., Quackenbush J., Spiegelman N., et al. Comprehensive Biostatistical Analysis of CpG Island Methylator Phenotype in Colorectal Cancer Using a Large Population-Based Sample. PLoS ONE. 2008;3:e3698. doi: 10.1371/journal.pone.0003698. PubMed DOI PMC

English D.R., Young J.P., Simpson J.A., Jenkins M.A., Southey M.C., Walsh M.D., Buchanan D.D., Barker M.A., Haydon A.M., Royce S.G., et al. Ethnicity and Risk for Colorectal Cancers Showing Somatic BRAF V600E Mutation or CpG Island Methylator Phenotype. Cancer Epidemiol. Biomarkers Prev. 2008;2008. 17:1774–1780. doi: 10.1158/1055-9965.EPI-08-0091. PubMed DOI

Samowitz W.S., Albertsen H., Herrick J., Levin T.R., Sweeney C., Murtaugh M., Wolff R.K., Slattery M.L. Evaluation of a Large, Population-Based Sample Supports a CpG Island Methylator Phenotype in Colon Cancer. Gastroenterology. 2005;129:837–845. doi: 10.1053/j.gastro.2005.06.020. PubMed DOI

Goel A., Nagasaka T., Arnold C.N., Inoue T., Hamilton C., Niedzwiecki D., Compton C., Mayer R.J., Goldberg R., Bertagnolli M.M., et al. The CpG Island Methylator Phenotype and Chromosomal Instability Are Inversely Correlated in Sporadic Colorectal Cancer. Gastroenterology. 2007;132:127–138. doi: 10.1053/j.gastro.2006.09.018. PubMed DOI

Cheng Y.-W., Pincas H., Bacolod M.D., Schemmann G., Giardina S.F., Huang J., Barral S., Idrees K., Khan S.A., Zeng Z., et al. CpG island methylator phenotype associates with low-degree chromosomal abnormalities in colorectal cancer. Clin. Cancer Res. 2008;14:6005–6013. doi: 10.1158/1078-0432.CCR-08-0216. PubMed DOI PMC

Leggett B., Whitehall V.L.J. Role of the Serrated Pathway in Colorectal Cancer Pathogenesis. Gastroenterology. 2010;138:2088–2100. doi: 10.1053/j.gastro.2009.12.066. PubMed DOI

Young J., Jass J.R. The Case for a Genetic Predisposition to Serrated Neoplasia in the Colorectum: Hypothesis and Review of the Literature. Cancer Epidemiol. Biomark. Prev. 2006;15:1778–1784. doi: 10.1158/1055-9965.EPI-06-0164. PubMed DOI

Ogino S., Kawasaki T., Kirkner G.J., Loda M., Fuchs C.S. CpG Island Methylator Phenotype-Low (CIMP-Low) in Colorectal Cancer: Possible Associations with Male Sex and KRAS Mutations. J. Mol. Diagn. 2006;8:582–588. doi: 10.2353/jmoldx.2006.060082. PubMed DOI PMC

Takane K., Akagi K., Fukuyo M., Yagi K., Takayama T., Kaneda A. DNA methylation epigenotype and clinical features ofNRAS-mutation(+) colorectal cancer. Cancer Med. 2017;6:1023–1035. doi: 10.1002/cam4.1061. PubMed DOI PMC

Yagi K., Akagi K., Hayashi H., Nagae G., Tsuji S., Isagawa T., Midorikawa Y., Nishimura Y., Sakamoto H., Seto Y., et al. Three DNA Methylation Epigenotypes in Human Colorectal Cancer. Clin. Cancer Res. 2009;16:21–33. doi: 10.1158/1078-0432.CCR-09-2006. PubMed DOI

Sakai E., Ohata K., Chiba H., Matsuhashi N., Doi N., Fukushima J., Endo H., Takahashi H., Tsuji S., Yagi K., et al. Methylation epigenotypes and genetic features in colorectal laterally spreading tumors. Int. J. Cancer. 2014;135:1586–1595. doi: 10.1002/ijc.28814. PubMed DOI

Fennell L.J., Dumenil T., Wockner L., Hartel G., Nones K., Bond C., Borowsky J., Liu C., McKeone D., Bowdler L., et al. Integrative Genome-Scale DNA Methylation Analysis of a Large and Unselected Cohort Reveals 5 Distinct Subtypes of Colorectal Adenocarcinomas. Cell. Mol. Gastroenterol. Hepatol. 2019;8:269–290. doi: 10.1016/j.jcmgh.2019.04.002. PubMed DOI PMC

Jass J.R. Classification of colorectal cancer based on correlation of clinical, morphological and molecular features. Histopathology. 2007;50:113–130. doi: 10.1111/j.1365-2559.2006.02549.x. PubMed DOI

Walther A., Johnstone E., Swanton C., Midgley R., Tomlinson I., Kerr R.S. Genetic prognostic and predictive markers in colorectal cancer. Nat. Rev. Cancer. 2009;9:489–499. doi: 10.1038/nrc2645. PubMed DOI

Limsui D., Vierkant R., Tillmans L.S., Wang A.H., Weisenberger D.J., Laird P.W., Lynch C.F., Anderson K.E., French A.J., Haile R.W., et al. Cigarette Smoking and Colorectal Cancer Risk by Molecularly Defined Subtypes. J. Natl. Cancer Inst. 2010;102:1012–1022. doi: 10.1093/jnci/djq201. PubMed DOI PMC

Hinoue T., Weisenberger D.J., Lange C.P., Shen H., Byun H.-M., Berg D.V.D., Malik S., Pan F., Noushmehr H., Van Dijk C.M., et al. Genome-scale analysis of aberrant DNA methylation in colorectal cancer. Genome Res. 2011;22:271–282. doi: 10.1101/gr.117523.110. PubMed DOI PMC

Ogino S., Goel A. Molecular Classification and Correlates in Colorectal Cancer. J. Mol. Diagn. 2008;10:13–27. doi: 10.2353/jmoldx.2008.070082. PubMed DOI PMC

Melo F.D.S.E., Wang X., Jansen M., Fessler E., Trinh A., De Rooij L.P.M.H., De Jong J.H., De Boer O.J., Van Leersum R., Bijlsma M.F., et al. Poor-prognosis colon cancer is defined by a molecularly distinct subtype and develops from serrated precursor lesions. Nat. Med. 2013;19:614–618. doi: 10.1038/nm.3174. PubMed DOI

Melo F.D.S.E., Colak S., Buikhuisen J., Koster J., Cameron K., De Jong J.H., Tuynman J.B., Prasetyanti P.R., Fessler E., Bergh S.P.V.D., et al. Methylation of Cancer-Stem-Cell-Associated Wnt Target Genes Predicts Poor Prognosis in Colorectal Cancer Patients. Cell Stem Cell. 2011;9:476–485. doi: 10.1016/j.stem.2011.10.008. PubMed DOI

Kaneda A., Yagi K. Two groups of DNA methylation markers to classify colorectal cancer into three epigenotypes. Cancer Sci. 2011;102:18–24. doi: 10.1111/j.1349-7006.2010.01712.x. PubMed DOI

Guinney J., Dienstmann R., Wang X., De Reyniès A., Schlicker A., Soneson C., Marisa L., Roepman P., Nyamundanda G., Angelino P., et al. The consensus molecular subtypes of colorectal cancer. Nat. Med. 2015;21:1350–1356. doi: 10.1038/nm.3967. PubMed DOI PMC

Marisa L., De Reynies A., Duval A., Selves J., Gaub M.P., Vescovo L., Etienne-Grimaldi M.-C., Schiappa R., Guenot D., Ayadi M., et al. Gene Expression Classification of Colon Cancer into Molecular Subtypes: Characterization, Validation, and Prognostic Value. PLoS Med. 2013;10:e1001453. doi: 10.1371/journal.pmed.1001453. PubMed DOI PMC

Budinská E., Popovici V., Tejpar S., D’Ario G., Lapique N., Sikora K.O., Di Narzo A.F., Yan P., Hodgson J.G., Weinrich S., et al. Gene expression patterns unveil a new level of molecular heterogeneity in colorectal cancer. J. Pathol. 2013;231:63–76. doi: 10.1002/path.4212. PubMed DOI PMC

Kwon Y., Park M., Jang M., Yun S., Kim W.K., Kim S., Paik S., Lee H.J., Hong S., Kim T.I., et al. Prognosis of stage III colorectal carcinomas with FOLFOX adjuvant chemotherapy can be predicted by molecular subtype. Oncotarget. 2017;8:39367–39381. doi: 10.18632/oncotarget.17023. PubMed DOI PMC

Del Rio M., Mollevi C., Bibeau F., Vie N., Selves J., Emile J.-F., Roger P., Gongora C., Robert J., Tubiana-Mathieu N., et al. Molecular subtypes of metastatic colorectal cancer are associated with patient response to irinotecan-based therapies. Eur. J. Cancer. 2017;76:68–75. doi: 10.1016/j.ejca.2017.02.003. PubMed DOI

Mooi J., Wirapati P., Asher R., Lee C., Savas P.S., Price T., Townsend A., Hardingham J.E., Buchanan D., Williams D., et al. The prognostic impact of consensus molecular subtypes (CMS) and its predictive effects for bevacizumab benefit in metastatic colorectal cancer: Molecular analysis of the AGITG MAX clinical trial. Ann. Oncol. 2018;29:2240–2246. doi: 10.1093/annonc/mdy410. PubMed DOI

Dienstmann R., Salazar R., Tabernero J. The Evolution of Our Molecular Understanding of Colorectal Cancer: What We Are Doing Now, What the Future Holds, and How Tumor Profiling Is Just the Beginning. Am. Soc. Clin. Oncol. Educ. Book. 2014;34:91–99. doi: 10.14694/EdBook_AM.2014.34.91. PubMed DOI

Okita A., Takahashi S., Ouchi K., Inoue M., Watanabe M., Endo M., Honda H., Yamada Y., Ishioka C. Consensus molecular subtypes classification of colorectal cancer as a predictive factor for chemotherapeutic efficacy against metastatic colorectal cancer. Oncotarget. 2018;9:18698–18711. doi: 10.18632/oncotarget.24617. PubMed DOI PMC

Stintzing S., Wirapati P., Lenz H.-J., Neureiter D., Von Weikersthal L.F., Decker T., Kiani A., Kaiser F., Al-Batran S., Heintges T., et al. Consensus molecular subgroups (CMS) of colorectal cancer (CRC) and first-line efficacy of FOLFIRI plus cetuximab or bevacizumab in the FIRE3 (AIO KRK-0306) trial. Ann. Oncol. 2019;30:1796–1803. doi: 10.1093/annonc/mdz387. PubMed DOI PMC

Lenz H.-J., Ou F.-S., Venook A.P., Hochster H.S., Niedzwiecki D., Goldberg R.M., Mayer R.J., Bertagnolli M.M., Blanke C.D., Zemla T., et al. Impact of Consensus Molecular Subtype on Survival in Patients With Metastatic Colorectal Cancer: Results From CALGB/SWOG 80405 (Alliance) J. Clin. Oncol. 2019;37:1876–1885. doi: 10.1200/JCO.18.02258. PubMed DOI PMC

Arnold D., Lueza B., Douillard J.-Y., Peeters M., Lenz H.-J., Venook A., Heinemann V., Van Cutsem E., Pignon J.-P., Tabernero J., et al. Prognostic and predictive value of primary tumour side in patients with RAS wild-type metastatic colorectal cancer treated with chemotherapy and EGFR directed antibodies in six randomized trials. Ann. Oncol. 2017;28:1713–1729. doi: 10.1093/annonc/mdx175. PubMed DOI PMC

Trinh A., Trumpi K., Melo F.D.S.E., Wang X., De Jong J.H., Fessler E., Kuppen P.J., Reimers M.S., Swets M., Koopman M., et al. Practical and Robust Identification of Molecular Subtypes in Colorectal Cancer by Immunohistochemistry. Clin. Cancer Res. 2016;23:387–398. doi: 10.1158/1078-0432.CCR-16-0680. PubMed DOI

Aderka D., Stintzing S., Heinemann V. Explaining the unexplainable: Discrepancies in results from the CALGB/SWOG 80405 and FIRE-3 studies. Lancet Oncol. 2019;20:e274–e283. doi: 10.1016/S1470-2045(19)30172-X. PubMed DOI

Büchler T., Chloupkova R., Poprach A., Fiala O., Kiss I., Kopeckova K., Dusek L., Veskrnova V., Slavicek L., Kohoutek M., et al. Sequential therapy with bevacizumab and EGFR inhibitors for metastatic colorectal carcinoma: A national registry-based analysis. Cancer Manag. Res. 2018;11:359–368. doi: 10.2147/CMAR.S183093. PubMed DOI PMC

Marisa L., Ayadi M., Balogoun R., Pilati C., Le Malicot K., Lepage C., Emile J.-F., Salazar R., Aust D.E., Duval A., et al. Clinical utility of colon cancer molecular subtypes: Validation of two main colorectal molecular classifications on the PETACC-8 phase III trial cohort. J. Clin. Oncol. 2017;35:3509. doi: 10.1200/JCO.2017.35.15_suppl.3509. DOI

Yoshino T., Arnold D., Taniguchi H., Pentheroudakis G., Yamazaki K., Xu R.-H., Kim T., Ismail F., Tan I., Yeh K.-H., et al. Pan-Asian adapted ESMO consensus guidelines for the management of patients with metastatic colorectal cancer: A JSMO–ESMO initiative endorsed by CSCO, KACO, MOS, SSO and TOS. Ann. Oncol. 2018;29:44–70. doi: 10.1093/annonc/mdx738. PubMed DOI

Van Cutsem E., Cervantes A., Adam R., Sobrero A., Van Krieken J.H.J., Aderka D., Aguilar E.A., Bardelli A., Benson A., Bodoky G., et al. ESMO consensus guidelines for the management of patients with metastatic colorectal cancer. Ann. Oncol. 2016;27:1386–1422. doi: 10.1093/annonc/mdw235. PubMed DOI

Sinicrope F., Foster N.R., Thibodeau S.N., Marsoni S., Monges G., Labianca R., Yothers G., Allegra C., Moore M.J., Gallinger S., et al. DNA Mismatch Repair Status and Colon Cancer Recurrence and Survival in Clinical Trials of 5-Fluorouracil-Based Adjuvant Therapy. J. Natl. Cancer Inst. 2011;103:863–875. doi: 10.1093/jnci/djr153. PubMed DOI PMC

Bender U., Rho Y., Barrera I., Aghajanyan S., Acoba J., Kavan P. Adjuvant therapy for stages II and III colon cancer: Risk stratification, treatment duration, and future directions. Curr. Oncol. 2019;26:S43–S52. doi: 10.3747/co.26.5605. PubMed DOI PMC

Evrard C., Tachon G., Randrian V., Karayan-Tapon L., Tougeron D., Tapon K. Microsatellite Instability: Diagnosis, Heterogeneity, Discordance, and Clinical Impact in Colorectal Cancer. Cancers. 2019;11:1567. doi: 10.3390/cancers11101567. PubMed DOI PMC

Le D.T., Uram J.N., Wang H., Bartlett B.R., Kemberling H., Eyring A.D., Skora A.D., Luber B.S., Azad N.S., Laheru D., et al. PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. N. Engl. J. Med. 2015;372:2509–2520. doi: 10.1056/NEJMoa1500596. PubMed DOI PMC

Venderbosch S., Nagtegaal I., Maughan T.S., Smith C.G., Cheadle J.P., Fisher D., Kaplan R., Quirke P., Seymour M.T., Richman S.D., et al. Mismatch repair status and BRAF mutation status in metastatic colorectal cancer patients: A pooled analysis of the CAIRO, CAIRO2, COIN and FOCUS studies. Clin. Cancer Res. 2014;20:5322–5330. doi: 10.1158/1078-0432.CCR-14-0332. PubMed DOI PMC

Nojadeh J.N., Behrouz Sharif S., Sakhinia E. Microsatellite instability in colorectal cancer. EXCLI J. 2018;17:159–168. PubMed PMC

Kane M.F., Loda M., Gaida G.M., Lipman J., Mishra R., Goldman H., Jessup J.M., Kolodner R. Methylation of the hMLH1 promoter correlates with lack of expression of hMLH1 in sporadic colon tumors and mismatch repair-defective human tumor cell lines. Cancer Res. 1997;57:808–811. PubMed

Boland C.R., Thibodeau S.N., Hamilton S.R., Sidransky D., Eshleman J.R., Burt R.W., Meltzer S.J., A Rodriguez-Bigas M., Fodde R., Ranzani G.N., et al. A National Cancer Institute Workshop on Microsatellite Instability for cancer detection and familial predisposition: Development of international criteria for the determination of microsatellite instability in colorectal cancer. Cancer Res. 1998;58:5248–5257. PubMed

Perucho M. Microsatellite instability: The mutator that mutates the other mutator. Nat. Med. 1996;2:630–631. doi: 10.1038/nm0696-630. PubMed DOI

Tougeron D., Mouillet G., Trouilloud I., LeComte T., Coriat R., Aparicio T., Guetz G.D., Lécaille C., Artru P., Sickersen G., et al. Efficacy of Adjuvant Chemotherapy in Colon Cancer With Microsatellite Instability: A Large Multicenter AGEO Study. J. Natl. Cancer Inst. 2016;108 doi: 10.1093/jnci/djv438. PubMed DOI

Jover R., Nguyen T., Pérez–Carbonell L., Zapater P., Payá A., Alenda C., Rojas E., Cubiella J., Balaguer F., Morillas J.D., et al. 5-Fluorouracil adjuvant chemotherapy does not increase survival in patients with CpG island methylator phenotype colorectal cancer. Gastroenterology. 2010;140:1174–1181. doi: 10.1053/j.gastro.2010.12.035. PubMed DOI PMC

Schwitalle Y., Linnebacher M., Ripberger E., Gebert J., Doeberitz M.V.K. Immunogenic peptides generated by frameshift mutations in DNA mismatch repair-deficient cancer cells. Cancer Immun. 2004;4:14. PubMed

Linnebacher M., Gebert J., Rudy W., Woerner S., Yuan Y.P., Bork P., Doeberitz M.V.K., Yuan Y. Frameshift peptide-derived T-cell epitopes: A source of novel tumor-specific antigens. Int. J. Cancer. 2001;93:6–11. doi: 10.1002/ijc.1298. PubMed DOI

Ishikawa T., Fujita T., Suzuki Y., Okabe S., Yuasa Y., Iwai T., Kawakami Y. Tumor-specific immunological recognition of frameshift-mutated peptides in colon cancer with microsatellite instability. Cancer Res. 2003;63:5564–5572. PubMed

Saeterdal I., Bjørheim J., Lislerud K., Gjertsen M.K., Bukholm I.K., Olsen O.C., Nesland J.M., Eriksen J.A., Møller M., Lindblom A., et al. Frameshift-mutation-derived peptides as tumor-specific antigens in inherited and spontaneous colorectal cancer. Proc. Natl. Acad. Sci. USA. 2001;98:13255–13260. doi: 10.1073/pnas.231326898. PubMed DOI PMC

Brunner-Weinzierl M.C., Rudd C.E. CTLA-4 and PD-1 Control of T-Cell Motility and Migration: Implications for Tumor Immunotherapy. Front. Immunol. 2018;9:2737. doi: 10.3389/fimmu.2018.02737. PubMed DOI PMC

Overman M.J., McDermott R., Leach J.L., Lonardi S., Lenz H.-J., Morse M.A., Desai J., Hill A., Axelson M., Moss R.A., et al. Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): An open-label, multicentre, phase 2 study. Lancet Oncol. 2017;18:1182–1191. doi: 10.1016/S1470-2045(17)30422-9. PubMed DOI PMC

Esteller M., García-Foncillas J., Andion E., Goodman S.N., Hidalgo O.F., Vanaclocha V., Baylin S.B., Herman J.G. Inactivation of the DNA-Repair GeneMGMTand the Clinical Response of Gliomas to Alkylating Agents. N. Engl. J. Med. 2000;343:1350–1354. doi: 10.1056/NEJM200011093431901. PubMed DOI

Amatu A., Sartore-Bianchi A., Moutinho C., Belotti A., Bencardino K., Chirico G., Cassingena A., Rusconi F., Esposito A., Nichelatti M., et al. Promoter CpG Island Hypermethylation of the DNA Repair Enzyme MGMT Predicts Clinical Response to Dacarbazine in a Phase II Study for Metastatic Colorectal Cancer. Clin. Cancer Res. 2013;19:2265–2272. doi: 10.1158/1078-0432.CCR-12-3518. PubMed DOI

Fornaro L., Vivaldi C., Caparello C., Musettini G., Baldini E., Masi G., Falcone A. Pharmacoepigenetics in gastrointestinal tumors: MGMT methylation and beyond. Front Biosci. 2016;8:170–180. doi: 10.2741/e758. PubMed DOI

Nagasaka T., Sharp G.B., Notohara K., Kambara T., Sasamoto H., Isozaki H., Macphee D.G., Jass J.R., Tanaka N., Matsubara N. Hypermethylation of O6-methylguanine-DNA methyltransferase promoter may predict nonrecurrence after chemotherapy in colorectal cancer cases. Clin. Cancer Res. 2003;9:5306–5312. PubMed

Sun W., Sun Y., Zhu M., Wang Z., Zhang H., Xin Y., Jiang G., Guo X., Zhang Z., Liu Y. The role of plasma cell-free DNA detection in predicting preoperative chemoradiotherapy response in rectal cancer patients. Oncol. Rep. 2013;31:1466–1472. doi: 10.3892/or.2013.2949. PubMed DOI

Kawakami K., Matsunoki A., Kaneko M., Saito K., Watanabe G., Minamoto T. Long interspersed nuclear element-1 hypomethylation is a potential biomarker for the prediction of response to oral fluoropyrimidines in microsatellite stable and CpG island methylator phenotype-negative colorectal cancer. Cancer Sci. 2010;102:166–174. doi: 10.1111/j.1349-7006.2010.01776.x. PubMed DOI

Kaneko M., Kotake M., Bando H., Yamada T., Takemura H., Minamoto T. Prognostic and predictive significance of long interspersed nucleotide element-1 methylation in advanced-stage colorectal cancer. BMC Cancer. 2016;16:945. doi: 10.1186/s12885-016-2984-8. PubMed DOI PMC

Jiang G., Lin J., Wang W., Sun M., Chen K., Wang F. WNT5A Promoter Methylation Is Associated with Better Responses and Longer Progression-Free Survival in Colorectal Cancer Patients Treated with 5-Fluorouracil-Based Chemotherapy. Genet. Test. Mol. Biomark. 2017;21:74–79. doi: 10.1089/gtmb.2016.0162. PubMed DOI

Chang S.-Y., Kuo C.-C., Wu C.-C., Hsiao C.-W., Hu J.-M., Hsu C.-H., Chou Y.-C., Shih Y.-L., Lin Y.-W. NKX6.1 hypermethylation predicts the outcome of stage II colorectal cancer patients undergoing chemotherapy. Genes Chromosomes Cancer. 2018;57:268–277. doi: 10.1002/gcc.22529. PubMed DOI

Ebert M.P., Tänzer M., Balluff B., Burgermeister E., Kretzschmar A.K., Hughes D.J., Tetzner R., Lofton-Day C., Rosenberg R., Reinacher-Schick A., et al. TFAP2E–DKK4and Chemoresistance in Colorectal Cancer. N. Engl. J. Med. 2012;366:44–53. doi: 10.1056/NEJMoa1009473. PubMed DOI

Perez-Carbonell L., Balaguer F., Toiyama Y., Egoavil C.M., Rojas E., Guarinos C., Andreu M., Llor X., Castells A., Jover R., et al. IGFBP3 Methylation Is a Novel Diagnostic and Predictive Biomarker in Colorectal Cancer. PLoS ONE. 2014;9:e104285. doi: 10.1371/journal.pone.0104285. PubMed DOI PMC

Pfütze K., Benner A., Hoffmeister M., Jansen L., Yang R., Bläker H., Herpel E., Ulrich A., Ulrich C.M., Chang-Claude J., et al. Methylation status at HYAL2 predicts overall and progression-free survival of colon cancer patients under 5-FU chemotherapy. Genomics. 2015;106:348–354. doi: 10.1016/j.ygeno.2015.10.002. PubMed DOI

Shimizu S., Iida S., Ishiguro M., Uetake H., Ishikawa T., Takagi Y., Kobayashi H., Higuchi T., Enomoto M., Mogushi K., et al. Methylated BNIP3 gene in colorectal cancer prognosis. Oncol. Lett. 2010;1:865–872. doi: 10.3892/ol_00000153. PubMed DOI PMC

Han S.-W., Lee H.-J., Bae J.M., Cho N.-Y., Lee K.-H., Kim T.-Y., Oh D.-Y., Im S.-A., Bang Y.-J., Jeong S.-Y., et al. Methylation and microsatellite status and recurrence following adjuvant FOLFOX in colorectal cancer. Int. J. Cancer. 2012;132:2209–2216. doi: 10.1002/ijc.27888. PubMed DOI

Kim S.H., Park K.H., Shin S.J., Lee K.Y., Kim T.I., Kim N.K., Rha S.Y., Roh J.K., Ahn J.B. p16 Hypermethylation and KRAS Mutation Are Independent Predictors of Cetuximab Plus FOLFIRI Chemotherapy in Patients with Metastatic Colorectal Cancer. Cancer Res. Treat. 2016;48:208–215. doi: 10.4143/crt.2014.314. PubMed DOI PMC

Sun X., Yuan W., Hao F., Zhuang W. Promoter Methylation of RASSF1A indicates Prognosis for Patients with Stage II and III Colorectal Cancer Treated with Oxaliplatin-Based Chemotherapy. Med. Sci. Monit. 2017;23:5389–5395. doi: 10.12659/MSM.903927. PubMed DOI PMC

Nagai Y., Sunami E., Yamamoto Y., Hata K., Okada S., Murono K., Yasuda K., Otani K., Nishikawa T., Tanaka T., et al. LINE-1 hypomethylation status of circulating cell-free DNA in plasma as a biomarker for colorectal cancer. Oncotarget. 2017;8:11906–11916. doi: 10.18632/oncotarget.14439. PubMed DOI PMC

Cha Y., Kim K.-J., Han S.-W., Rhee Y.Y., Bae J.M., Wen X., Cho N.-Y., Lee D.-W., Lee K.-H., Kim T.-Y., et al. Adverse prognostic impact of the CpG island methylator phenotype in metastatic colorectal cancer. Br. J. Cancer. 2016;115:164–171. doi: 10.1038/bjc.2016.176. PubMed DOI PMC

Cohen S.A., Wu C., Yu M., Gourgioti G., Wirtz R., Raptou G., Gkakou C., Kotoula V., Pentheroudakis G., Papaxoinis G., et al. Evaluation of CpG Island Methylator Phenotype as a Biomarker in Colorectal Cancer Treated With Adjuvant Oxaliplatin. Clin. Color. Cancer. 2015;15:164–169. doi: 10.1016/j.clcc.2015.10.005. PubMed DOI PMC

Hall P.A., Russell S.H. The pathobiology of the septin gene family. J. Pathol. 2004;204:489–505. doi: 10.1002/path.1654. PubMed DOI

Lofton-Day C., Model F., Devos T., Tetzner R., Distler J., Schuster M., Song X., Lesche R., Liebenberg V., Ebert M., et al. DNA Methylation Biomarkers for Blood-Based Colorectal Cancer Screening. Clin. Chem. 2008;54:414–423. doi: 10.1373/clinchem.2007.095992. PubMed DOI

Devos T., Tetzner R., Model F., Weiss G., Schuster M., Distler J., Steiger K.V., Grützmann R., Pilarsky C., Habermann J.K., et al. Circulating Methylated SEPT9 DNA in Plasma Is a Biomarker for Colorectal Cancer. Clin. Chem. 2009;55:1337–1346. doi: 10.1373/clinchem.2008.115808. PubMed DOI

Lee H.S., Hwang S.M., Kim T.S., Kim D.-W., Park D.J., Kang S.-B., Kim H.-H., Park K.U. Circulating Methylated Septin 9 Nucleic Acid in the Plasma of Patients with Gastrointestinal Cancer in the Stomach and Colon. Transl. Oncol. 2013;6:290–IN4. doi: 10.1593/tlo.13118. PubMed DOI PMC

Tham C., Chew M., Soong R., Lim J., Ang M., Tang C., Zhao Y., Ong S.Y.K., Liu Y. Postoperative serum methylation levels of TAC1 and SEPT9 are independent predictors of recurrence and survival of patients with colorectal cancer. Cancer. 2014;120:3131–3141. doi: 10.1002/cncr.28802. PubMed DOI

Bhangu J.S., Beer A., Mittlböck M., Tamandl D., Walter P., Schönthaler S., Taghizadeh H., Stremitzer S., Kaczirek K., Gruenberger T., et al. Circulating Free Methylated Tumor DNA Markers for Sensitive Assessment of Tumor Burden and Early Response Monitoring in Patients Receiving Systemic Chemotherapy for Colorectal Cancer Liver Metastasis. Ann. Surg. 2018;268:894–902. doi: 10.1097/SLA.0000000000002901. PubMed DOI

Draht M.X.G., Goudkade D., Koch A., Grabsch H.I., Weijenberg M.P., Van Engeland M., Melotte V., Smits K. Prognostic DNA methylation markers for sporadic colorectal cancer: A systematic review. Clin. Epigenetics. 2018;10:35. doi: 10.1186/s13148-018-0461-8. PubMed DOI PMC

Ma Z., Williams M., Cheng Y.Y., Leung W.K. Roles of Methylated DNA Biomarkers in Patients with Colorectal Cancer. Dis. Markers. 2019;2019:1–8. doi: 10.1155/2019/2673543. PubMed DOI PMC

Yi J.M., Dhir M., Van Neste L., Downing S.R., Jeschke J., Glöckner S.C., Calmon M.D.F., Hooker C.M., Funes J.M., Boshoff C., et al. Genomic and epigenomic integration identifies a prognostic signature in colon cancer. Clin. Cancer Res. 2011;17:1535–1545. doi: 10.1158/1078-0432.CCR-10-2509. PubMed DOI PMC

Fu T., Pappou E.P., Guzzetta A.A., Calmon M.D.F., Sun L., Herrera A., Li F., Wolfgang C.L., Baylin S.B., Iacobuzio-Donahue C.A., et al. IGFBP-3 Gene Methylation in Primary Tumor Predicts Recurrence of Stage II Colorectal Cancers. Ann. Surg. 2016;263:337–344. doi: 10.1097/SLA.0000000000001204. PubMed DOI PMC

Esteller M., González S., Risques R.A., Marcuello E., Mangues R., Germà J.R., Herman J.G., Capellá G., Peinado M.A. K-ras and p16 Aberrations Confer Poor Prognosis in Human Colorectal Cancer. J. Clin. Oncol. 2001;19:299–304. doi: 10.1200/JCO.2001.19.2.299. PubMed DOI

Wettergren Y., Odin E., Nilsson S., Carlsson G., Gustavsson B. p16INK4a Gene Promoter Hypermethylation in Mucosa as a Prognostic Factor for Patients with Colorectal Cancer. Mol. Med. 2008;14:412–421. doi: 10.2119/2007-00096.Wettergren. PubMed DOI PMC

Kohonen-Corish M.R., Tseung J., Chan C., Currey N., Dent O.F., Clarke S., Bokey L., Chapuis P.H. KRAS mutations and CDKN2A promoter methylation show an interactive adverse effect on survival and predict recurrence of rectal cancer. Int. J. Cancer. 2014;134:2820–2828. doi: 10.1002/ijc.28619. PubMed DOI

Kim S.H., Park K.H., Shin S.J., Lee K.Y., Kim T.I., Kim N.K., Rha S.Y., Ahn J.B. CpG Island Methylator Phenotype and Methylation of Wnt Pathway Genes Together Predict Survival in Patients with Colorectal Cancer. Yonsei Med. J. 2018;59:588–594. doi: 10.3349/ymj.2018.59.5.588. PubMed DOI PMC

Miladi-Abdennadher I., Abdelmaksoud-Damak R., Ayadi L., Khabir A., Frikha F., Kallel L., Frikha M., Sellami-Boudawara T., Gargouri A., Mokdad-Gargouri R. Aberrant methylation of hMLH1 and p16INK4a in Tunisian patients with sporadic colorectal adenocarcinoma. Biosci. Rep. 2011;31:257–264. doi: 10.1042/BSR20100023. PubMed DOI

Jensen L.H., Rasmussen A.A., Byriel L., Kuramochi H., Crüger D.G., Lindebjerg J., Danenberg P.V., Jakobsen A., Danenberg K. Regulation of MLH1 mRNA and protein expression by promoter methylation in primary colorectal cancer: A descriptive and prognostic cancer marker study. Cell. Oncol. 2013;36:411–419. doi: 10.1007/s13402-013-0148-2. PubMed DOI

Iida S., Kato S., Ishiguro M., Matsuyama T., Ishikawa T., Kobayashi H., Higuchi T., Uetake H., Enomoto M., Sugihara K. PIK3CA mutation and methylation influences the outcome of colorectal cancer. Oncol. Lett. 2011;3:565–570. doi: 10.3892/ol.2011.544. PubMed DOI PMC

Wang Z., Yuan X., Jiao N., Zhu H., Zhang Y., Tong J. CDH13 and FLBN3 Gene Methylation are Associated with Poor Prognosis in Colorectal Cancer. Pathol. Oncol. Res. 2011;18:263–270. doi: 10.1007/s12253-011-9437-0. PubMed DOI

Kuan J.C., Wu C.C., Sun C.A., Chu C.M., Lin F.G., Hsu C.-H., Kan P.-C., Lin S.-C., Yang T., Chou Y.-C. DNA Methylation Combinations in Adjacent Normal Colon Tissue Predict Cancer Recurrence: Evidence from a Clinical Cohort Study. PLoS ONE. 2015;10:e0123396. doi: 10.1371/journal.pone.0123396. PubMed DOI PMC

Cha Y., Kim S.Y., Yeo H.Y., Baek J.Y., Choi M.K., Jung K.-H., Dong S.M., Chang H.J. Association of CHFR Promoter Methylation with Treatment Outcomes of Irinotecan-Based Chemotherapy in Metastatic Colorectal Cancer. Neoplasia. 2018;21:146–155. doi: 10.1016/j.neo.2018.11.010. PubMed DOI PMC

Robertson K.D., Jones P.A. DNA methylation: Past, present and future directions. Carcinogensis. 2000;21:461–467. doi: 10.1093/carcin/21.3.461. PubMed DOI

Cheray M., Pacaud R., Hervouet E., Vallette F., Cartron P.-F. DNMT Inhibitors in Cancer, Current Treatments and Future Promising Approach: Inhibition of Specific DNMT-Including Complexes. Epigenetic Diagn. Ther. 2015;1:37–48. doi: 10.2174/2214083201666150221002056. DOI

Kaminskas E., Farrell A., Wang Y.-C., Sridhara R., Pazdur R. FDA Drug Approval Summary: Azacitidine (5-azacytidine, VidazaTM) for Injectable Suspension. Oncologist. 2005;10:176–182. doi: 10.1634/theoncologist.10-3-176. PubMed DOI

Glover A.B., Leyland-Jones B.R., Chun H.G., Davies B., Hoth D.F. Azacitidine: 10 years later. Cancer Treat. Rep. 1987;71:737–746. PubMed

Stresemann C., Lyko F. Modes of action of the DNA methyltransferase inhibitors azacytidine and decitabine. Int. J. Cancer. 2008;123:8–13. doi: 10.1002/ijc.23607. PubMed DOI

Momparler R.L., Momparler L.F., Samson J. Comparison of the antileukemic activity of 5-AZA-2′-deoxycytidine, 1-beta-D-arabinofuranosylcytosine and 5-azacytidine against L1210 leukemia. Leuk. Res. 1984;8:1043–1049. doi: 10.1016/0145-2126(84)90059-6. PubMed DOI

Qin T., Jelinek J., Si J., Shu J., Issa J.P. Mechanisms of resistance to 5-aza-2′-deoxycytidine in human cancer cell lines. Blood. 2009;113:659–667. doi: 10.1182/blood-2008-02-140038. PubMed DOI PMC

Issa J.-P., Gharibyan V., Cortes J., Jelinek J., Morris G., Verstovsek S., Talpaz M., Garcia-Manero G., Kantarjian H.M. Phase II Study of Low-Dose Decitabine in Patients With Chronic Myelogenous Leukemia Resistant to Imatinib Mesylate. J. Clin. Oncol. 2005;23:3948–3956. doi: 10.1200/JCO.2005.11.981. PubMed DOI

Juttermann R., Li E., Jaenisch R. Toxicity of 5-aza-2′-deoxycytidine to mammalian cells is mediated primarily by covalent trapping of DNA methyltransferase rather than DNA demethylation. Proc. Natl. Acad. Sci. USA. 1994;91:11797–11801. doi: 10.1073/pnas.91.25.11797. PubMed DOI PMC

Derissen E.J., Beijnen J.H., Schellens J.H.M. Concise Drug Review: Azacitidine and Decitabine. Oncologist. 2013;18:619–624. doi: 10.1634/theoncologist.2012-0465. PubMed DOI PMC

Daher-Reyes G.S., Merchan B.M., Yee K.W.L. Guadecitabine (SGI-110): An investigational drug for the treatment of myelodysplastic syndrome and acute myeloid leukemia. Expert Opin. Investig. Drugs. 2019;28:835–849. doi: 10.1080/13543784.2019.1667331. PubMed DOI

Chuang J.C., Warner S.L., Vollmer D., Vankayalapati H., Redkar S., Bearss D., Qiu X., Yoo C.B., Jones P.A. S110, a 5-Aza-2′-deoxycytidine-containing dinucleotide, is an effective DNA methylation inhibitor in vivo and can reduce tumor growth. Mol. Cancer Ther. 2010;9:1443–1450. doi: 10.1158/1535-7163.MCT-09-1048. PubMed DOI PMC

Newlands E., Stevens M., Wedge S., Wheelhouse R.T., Brock C. Temozolomide: A review of its discovery, chemical properties, pre-clinical development and clinical trials. Cancer Treat. Rev. 1997;23:35–61. doi: 10.1016/S0305-7372(97)90019-0. PubMed DOI

Villano J.L., Seery T.E., Bressler L.R. Temozolomide in malignant gliomas: Current use and future targets. Cancer Chemother. Pharmacol. 2009;64:647–655. doi: 10.1007/s00280-009-1050-5. PubMed DOI

Cohen M.H., Johnson J.R., Pazdur R. Food and Drug Administration Drug Approval Summary: Temozolomide Plus Radiation Therapy for the Treatment of Newly Diagnosed Glioblastoma Multiforme. Clin. Cancer Res. 2005;11:6767–6771. doi: 10.1158/1078-0432.CCR-05-0722. PubMed DOI

Patnaik S. Anupriya Drugs Targeting Epigenetic Modifications and Plausible Therapeutic Strategies Against Colorectal Cancer. Front. Pharmacol. 2019;10:588. doi: 10.3389/fphar.2019.00588. PubMed DOI PMC

Tse J.W., Jenkins L.J., Chionh F., Mariadason J.M. Aberrant DNA Methylation in Colorectal Cancer: What Should We Target? Trends Cancer. 2017;3:698–712. doi: 10.1016/j.trecan.2017.08.003. PubMed DOI

Yamashita K., Dai T., Dai Y., Yamamoto F., Perucho M. Genetics supersedes epigenetics in colon cancer phenotype. Cancer Cell. 2003;4:121–131. doi: 10.1016/S1535-6108(03)00190-9. PubMed DOI

Fink D., Aebi S., Howell S.B. The role of DNA mismatch repair in drug resistance. Clin. Cancer Res. 1998;4:1–6. PubMed

Li H., Chiappinelli K.B., Guzzetta A.A., Easwaran H., Yen R.-W.C., Vatapalli R., Topper M.J., Luo J., Connolly R.M., Azad N.S., et al. Immune regulation by low doses of the DNA methyltransferase inhibitor 5-azacitidine in common human epithelial cancers. Oncotarget. 2014;5:587–598. doi: 10.18632/oncotarget.1782. PubMed DOI PMC

Kuang C., Park Y., Bahary N., Sun W., Ohr J., Rhee J.C., Marks S.M., Beasley H.S., Shuai Y., Lin Y., et al. Biomarker analysis for UPCI 14–118: Phase II study of pembrolizumab in combination with azacitidine in patients with refractory metastatic colorectal cancer. J. Clin. Oncol. 2020;38:173. doi: 10.1200/JCO.2020.38.4_suppl.173. PubMed DOI

Jansen Y.J.L., Verset G., Schats K., Van Dam P.-J., Seremet T., Kockx M., Van Laethem J.-L.B., Neyns B. Phase I clinical trial of decitabine (5-aza-2′-deoxycytidine) administered by hepatic arterial infusion in patients with unresectable liver-predominant metastases. ESMO Open. 2019;4:e000464. doi: 10.1136/esmoopen-2018-000464. PubMed DOI PMC

Garrido-Laguna I., McGregor K.A., Wade M., Weis J., Gilcrease W., Burr L., Soldi R., Jakubowski L., Davidson C., Morrell G., et al. A phase I/II study of decitabine in combination with panitumumab in patients with wild-type (wt) KRAS metastatic colorectal cancer. Investig. New Drugs. 2013;31:1257–1264. doi: 10.1007/s10637-013-9947-6. PubMed DOI

Sharma A., Vatapalli R., Abdelfatah E., McMahon K.W., Kerner Z., Guzzetta A.A., Singh J., Zahnow C., Baylin S.B., Yerram S., et al. Hypomethylating agents synergize with irinotecan to improve response to chemotherapy in colorectal cancer cells. PLoS ONE. 2017;12:e0176139. doi: 10.1371/journal.pone.0176139. PubMed DOI PMC

Pishvaian M.J., Slack R.S., Jiang W., He A.R., Hwang J.J., Hankin A., Dorsch-Vogel K., Kukadiya D., Weiner L.M., Marshall J.L., et al. A phase 2 study of the PARP inhibitor veliparib plus temozolomide in patients with heavily pretreated metastatic colorectal cancer. Cancer. 2018;124:2337–2346. doi: 10.1002/cncr.31309. PubMed DOI PMC

Morano F., Corallo S., Niger M., Barault L., Milione M., Berenato R., Moretto R., Randon G., Antista M., Belfiore A., et al. Temozolomide and irinotecan (TEMIRI regimen) as salvage treatment of irinotecan-sensitive advanced colorectal cancer patients bearing MGMT methylation. Ann. Oncol. 2018;29:1800–1806. doi: 10.1093/annonc/mdy197. PubMed DOI

Pietrantonio F., Lobefaro R., Antista M., Lonardi S., Raimondi A., Morano F., Mosconi S., Rimassa L., Murgioni S., Sartore-Bianchi A., et al. Capecitabine and Temozolomide versus FOLFIRI in RAS-Mutated, MGMT-Methylated Metastatic Colorectal Cancer. Clin. Cancer Res. 2019;26:1017–1024. doi: 10.1158/1078-0432.CCR-19-3024. PubMed DOI

Hochhauser D., Glynne-Jones R., Potter V., Pathiraja K., Zhang Q., Zhang L., Sausville E.A., Grávalos C., Doyle T.J. A Phase II Study of Temozolomide in Patients with Advanced Aerodigestive Tract and Colorectal Cancers and Methylation of the O6-Methylguanine-DNA Methyltransferase Promoter. Mol. Cancer Ther. 2013;12:809–818. doi: 10.1158/1535-7163.MCT-12-0710. PubMed DOI

Stunnenberg H.G., Abrignani S., Adams D., de Almeida M., Altucci L., Amin V., Amit I., Antonarakis S.E., Aparicio S., Arima T., et al. The International Human Epigenome Consortium: A Blueprint for Scientific Collaboration and Discovery. Cell. 2016;167:1145–1149. doi: 10.1016/j.cell.2016.11.007. PubMed DOI

Abbott A. Project set to map marks on genome. Nature. 2010;463:596–597. doi: 10.1038/463596b. PubMed DOI

Cancer stem cell marker expression and methylation status in patients with colorectal cancer

DNA Mismatch Repair Gene Variants in Sporadic Solid Cancers

Distant Metastasis in Colorectal Cancer Patients-Do We Have New Predicting Clinicopathological and Molecular Biomarkers? A Comprehensive Review