DNA methylation in cancer

DNA methylation in cancer plays a variety of roles, helping to change the healthy regulation of gene expression to a disease pattern.

All mammalian cells descended from a fertilized egg (a zygote) share a common DNA sequence (except for new mutations in some lineages). However, during development and formation of different tissues epigenetic factors change. The changes include histone modifications, CpG island methylations and chromatin reorganizations which can cause the stable silencing or activation of particular genes.[1] Once differentiated tissues are formed, CpG island methylation is generally stably inherited from one cell division to the next through the DNA methylation maintenance machinery.[1]

In cancer, a number of mutational changes are found in protein coding genes. Colorectal cancers typically have 3 to 6 driver mutations and 33 to 66 hitchhiker or passenger mutations that silence protein expression in the genes affected.[2] However, transcriptional silencing may be more important than mutation in causing gene silencing in progression to cancer. In colorectal cancers about 600 to 800 genes are transcriptionally silenced, compared to adjacent normal-appearing tissues, by CpG island methylation. Transcriptional repression in cancer can also occur by other epigenetic mechanisms, such as altered expression of microRNAs.[3]

CpG islands are frequent control elements

CpG islands are commonly 200 to 2000 base pairs long, have a C:G base pair content >50%, and have frequent 5' → 3' CpG sequences. About 70% of human promoters located near the transcription start site of a gene contain a CpG island.[4][5]

Promoters located at a distance from the transcription start site of a gene also frequently contain CpG islands. The promoter of the DNA repair gene ERCC1, for instance, was identified and located about 5,400 nucleotides upstream of its coding region.[6] CpG islands also occur frequently in promoters for functional noncoding RNAs such as microRNAs and Long non-coding RNAs (lncRNAs).

Methylation of CpG islands in promoters stably silences genes

Genes can be silenced by multiple methylation of CpG sites in the CpG islands of their promoters.[7] Even if silencing of a gene is initiated by another mechanism, this often is followed by methylation of CpG sites in the promoter CpG island to stabilize the silencing of the gene.[7] On the other hand, hypomethylation of CpG islands in promoters can result in gene over-expression.

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 instance, in colon tumors compared to adjacent normal-appearing colonic mucosa, about 600 to 800 heavily methylated CpG islands occur in promoters of genes in the tumors while these CpG islands are not methylated in the adjacent mucosa.[8][9][10] In contrast, as Vogelstein et al.[2] point out, in a colorectal cancer there are typically only about 3 to 6 driver mutations and 33 to 66 hitchhiker or passenger mutations.

DNA repair gene silencing in cancer


In sporadic cancers, a DNA repair deficiency is occasionally found to be due to a mutation in a DNA repair gene. However, much more frequently, reduced or absent expression of a DNA repair gene in cancer is due to methylation of its promoter. For example, of 113 colorectal cancers examined, only four had a missense mutation in the DNA repair gene MGMT, while the majority had reduced MGMT expression due to methylation of the MGMT promoter region.[11] Similarly, among 119 cases of mismatch repair-deficient colorectal cancers that lacked DNA repair gene PMS2 expression, 6 had a mutation in the PMS2 gene, while for 103 PMS2 was deficient because its pairing partner MLH1 was repressed due to promoter methylation (PMS2 protein is unstable in the absence of MLH1).[12] In the remaining 10 cases, loss of PMS2 expression was likely due to epigenetic overexpression of the microRNA, miR-155, which down-regulates MLH1.[13]

Frequency of hypermethylation of DNA repair genes in cancer


Twenty-two DNA repair genes with hypermethylated promoters, and reduced or absent expression, were found to occur among 17 types of cancer, as listed in two review articles.[14][15] As listed in one of the reviews,[14] promoter hypermethylation of MGMT occurs frequently in a number of cancers including 93% of bladder cancers, 88% of stomach cancers, 74% of thyroid cancers, 40%-90% of colorectal cancers and 50% of brain cancers. That review also indicated promoter hypermethylation of LIG4, NEIL1, ATM, MLH1 or FANCB occurs at frequencies between 33% to 82% in one or more of head and neck cancers, non-small-cell lung cancers or non-small-cell lung cancer squamous cell carcinomas. The article Werner syndrome ATP-dependent helicase indicates the DNA repair gene WRN has a promoter that is frequently hypermethylated in a number of cancers, with hypermethylation occurring in 11% to 38% of colorectal, head and neck, stomach, prostate, breast, thyroid, non-Hodgkin lymphoma, chondrosarcoma and osteosarcoma cancers (see WRN).

Likely role of hypermethylation of DNA repair genes in cancer

As discussed by Jin and Roberston in their review,[15] silencing of a DNA repair gene by hypermethylation may be a very early step in progression to cancer. Such silencing is proposed to act similarly to a germ-line mutation in a DNA repair gene, and predisposes the cell and its descendants to progression to cancer. Another review[16] also indicated an early role for hypermethylation of DNA repair genes in cancer. If a gene necessary for DNA repair is hypermethylated, resulting in deficient DNA repair, DNA damages will accumulate. Increased DNA damage tends to cause increased errors during DNA synthesis, leading to mutations that can give rise to cancer.

If hypermethylation of a DNA repair gene is an early step in carcinogenesis, then it may also occur in the normal-appearing tissues surrounding the cancer from which the cancer arose (the field defect). See the table below.

Frequencies of hypermethylated promoters in DNA repair genes in sporadic cancers and in adjacent field defects
Cancer Gene Frequency in Cancer Frequency in Field DefectRef.
Colorectal MGMT 55%54%[17]
Colorectal MSH2 13%5% [18]
Colorectal WRN 29%13% [19]
Head and Neck MGMT 54%38%[20]
Head and Neck MLH1 33%25%[21]
Non-small cell lung cancer ATM 69%59%[22]
Non-small cell lung cancer MLH1 69%72%[22]
Stomach MGMT 88%78%[23]
Stomach MLH1 73%20%[24]
Esophagus MLH1 77%-100%23%-79%[25]

While DNA damages may give rise to mutations through error prone translesion synthesis, DNA damages can also give rise to epigenetic alterations during faulty DNA repair processes.[26][27][28][29] The DNA damages that accumulate due to hypermethylation of the promoters of DNA repair genes can be a source of the increased epigenetic alterations found in many genes in cancers.

In an early study, looking at a limited set of transcriptional promoters, Fernandez et al.[30] examined the DNA methylation profiles of 855 primary tumors. Comparing each tumor type with its corresponding normal tissue, 729 CpG island sites (55% of the 1322 CpG island sites evaluated) showed differential DNA methylation. Of these sites, 496 were hypermethylated (repressed) and 233 were hypomethylated (activated). Thus, there is a high level of promoter methylation alterations in tumors. Some of these alterations may contribute to cancer progression.

DNA methylation of microRNAs in cancer

In mammals, microRNAs (miRNAs) regulate the transcriptional activity of about 60% of protein-encoding genes.[31] Individual miRNAs can each target, and repress transcription of, on average, roughly 200 messenger RNAs of protein coding genes.[32] The promoters of about one third of the 167 miRNAs evaluated by Vrba et al.[33] in normal breast tissues were differentially hyper/hypo-methylated in breast cancers. A more recent study pointed out that the 167 miRNAs evaluated by Vrba et al. were only 10% of the miRNAs found expressed in breast tissues.[34] This later study found that 58% of the miRNAs in breast tissue had differentially methylated regions in their promoters in breast cancers, including 278 hypermethylated miRNAs and 802 hypomethylated miRNAs.

One miRNA that is over-expressed about 100-fold in breast cancers is miR-182.[35] MiR-182 targets the BRCA1 messenger RNA and may be a major cause of reduced BRCA1 protein expression in many breast cancers[36] (also see BRCA1).

microRNAs that control DNA methyltransferase genes in cancer

Some miRNAs target the messenger RNAs for DNA methyltransferase genes DNMT1, DNMT3A and DNMT3B, whose gene products are needed for initiating and stabilizing promoter methylations. As summarized in three reviews,[37][38][39] miRNAs miR-29a, miR-29b and miR-29c target DNMT3A and DNMT3B; miR-148a and miR-148b target DNMT3B; and miR-152 and miR-301 target DNMT1. In addition, miR-34b targets DNMT1 and the promoter of miR-34b itself is hypermethylated and under-expressed in the majority of prostate cancers.[40] When expression of these microRNAs is altered, they may also be a source of the hyper/hypo-methylation of the promoters of protein-coding genes in cancers.

References

  1. 1 2 Seisenberger S, Peat JR, Hore TA, Santos F, Dean W, Reik W (2013). "Reprogramming DNA methylation in the mammalian life cycle: building and breaking epigenetic barriers". Philos. Trans. R. Soc. Lond., B, Biol. Sci. 368 (1609): 20110330. doi:10.1098/rstb.2011.0330. PMC 3539359Freely accessible. PMID 23166394.
  2. 1 2 Vogelstein B, Papadopoulos N, Velculescu VE, Zhou S, Diaz LA, Kinzler KW (2013). "Cancer genome landscapes". Science. 339 (6127): 1546–58. doi:10.1126/science.1235122. PMC 3749880Freely accessible. PMID 23539594.
  3. Tessitore A, Cicciarelli G, Del Vecchio F, Gaggiano A, Verzella D, Fischietti M, Vecchiotti D, Capece D, Zazzeroni F, Alesse E (2014). "MicroRNAs in the DNA Damage/Repair Network and Cancer". Int J Genomics. 2014: 820248. doi:10.1155/2014/820248. PMC 3926391Freely accessible. PMID 24616890.
  4. Saxonov S, Berg P, Brutlag DL (2006). "A genome-wide analysis of CpG dinucleotides in the human genome distinguishes two distinct classes of promoters". Proc. Natl. Acad. Sci. U.S.A. 103 (5): 1412–7. doi:10.1073/pnas.0510310103. PMC 1345710Freely accessible. PMID 16432200.
  5. Deaton AM, Bird A (2011). "CpG islands and the regulation of transcription". Genes Dev. 25 (10): 1010–22. doi:10.1101/gad.2037511. PMC 3093116Freely accessible. PMID 21576262.
  6. Chen HY, Shao CJ, Chen FR, Kwan AL, Chen ZP (2010). "Role of ERCC1 promoter hypermethylation in drug resistance to cisplatin in human gliomas". Int. J. Cancer. 126 (8): 1944–54. doi:10.1002/ijc.24772. PMID 19626585.
  7. 1 2 Bird A (2002). "DNA methylation patterns and epigenetic memory". Genes Dev. 16 (1): 6–21. doi:10.1101/gad.947102. PMID 11782440.
  8. Illingworth RS, Gruenewald-Schneider U, Webb S, Kerr AR, James KD, Turner DJ, Smith C, Harrison DJ, Andrews R, Bird AP (2010). "Orphan CpG islands identify numerous conserved promoters in the mammalian genome". PLoS Genet. 6 (9): e1001134. doi:10.1371/journal.pgen.1001134. PMC 2944787Freely accessible. PMID 20885785.
  9. Wei J, Li G, Dang S, Zhou Y, Zeng K, Liu M (2016). "Discovery and Validation of Hypermethylated Markers for Colorectal Cancer". Dis. Markers. 2016: 2192853. doi:10.1155/2016/2192853. PMC 4963574Freely accessible. PMID 27493446.
  10. Beggs AD, Jones A, El-Bahrawy M, El-Bahwary M, Abulafi M, Hodgson SV, Tomlinson IP (2013). "Whole-genome methylation analysis of benign and malignant colorectal tumours". J. Pathol. 229 (5): 697–704. doi:10.1002/path.4132. PMC 3619233Freely accessible. PMID 23096130.
  11. Halford S, Rowan A, Sawyer E, Talbot I, Tomlinson I (June 2005). "O(6)-methylguanine methyltransferase in colorectal cancers: detection of mutations, loss of expression, and weak association with G:C>A:T transitions". Gut. 54 (6): 797–802. doi:10.1136/gut.2004.059535. PMC 1774551Freely accessible. PMID 15888787.
  12. Truninger K, Menigatti M, Luz J, et al. (May 2005). "Immunohistochemical analysis reveals high frequency of PMS2 defects in colorectal cancer". Gastroenterology. 128 (5): 1160–71. doi:10.1053/j.gastro.2005.01.056. PMID 15887099.
  13. Valeri N, Gasparini P, Fabbri M, et al. (April 2010). "Modulation of mismatch repair and genomic stability by miR-155". Proceedings of the National Academy of Sciences of the United States of America. 107 (15): 6982–7. Bibcode:2010PNAS..107.6982V. doi:10.1073/pnas.1002472107. JSTOR 25665289. PMC 2872463Freely accessible. PMID 20351277.
  14. 1 2 Carol Bernstein and Harris Bernstein (2015). Epigenetic Reduction of DNA Repair in Progression to Cancer, Advances in DNA Repair, Prof. Clark Chen (Ed.), ISBN 978-953-51-2209-8, InTech, Available from: http://www.intechopen.com/books/advances-in-dna-repair/epigenetic-reduction-of-dna-repair-in-progression-to-cancer
  15. 1 2 Jin B, Robertson KD (2013). "DNA methyltransferases, DNA damage repair, and cancer". Adv. Exp. Med. Biol. 754: 3–29. doi:10.1007/978-1-4419-9967-2_1. PMC 3707278Freely accessible. PMID 22956494.
  16. Bernstein C, Nfonsam V, Prasad AR, Bernstein H (2013). "Epigenetic field defects in progression to cancer". World J Gastrointest Oncol. 5 (3): 43–9. doi:10.4251/wjgo.v5.i3.43. PMC 3648662Freely accessible. PMID 23671730.
  17. Svrcek M, Buhard O, Colas C, Coulet F, Dumont S, Massaoudi I, Lamri A, Hamelin R, Cosnes J, Oliveira C, Seruca R, Gaub MP, Legrain M, Collura A, Lascols O, Tiret E, Fléjou JF, Duval A (November 2010). "Methylation tolerance due to an O6-methylguanine DNA methyltransferase (MGMT) field defect in the colonic mucosa: an initiating step in the development of mismatch repair-deficient colorectal cancers". Gut. 59 (11): 1516–26. doi:10.1136/gut.2009.194787. PMID 20947886.
  18. Lee KH, Lee JS, Nam JH, Choi C, Lee MC, Park CS, Juhng SW, Lee JH (2011). "Promoter methylation status of hMLH1, hMSH2, and MGMT genes in colorectal cancer associated with adenoma-carcinoma sequence". Langenbecks Arch Surg. 396 (7): 1017–26. doi:10.1007/s00423-011-0812-9. PMID 21706233.
  19. Kawasaki T, Ohnishi M, Suemoto Y, Kirkner GJ, Liu Z, Yamamoto H, Loda M, Fuchs CS, Ogino S (2008). "WRN promoter methylation possibly connects mucinous differentiation, microsatellite instability and CpG island methylator phenotype in colorectal cancer". Mod. Pathol. 21 (2): 150–8. doi:10.1038/modpathol.3800996. PMID 18084250.
  20. Paluszczak J, Misiak P, Wierzbicka M, Woźniak A, Baer-Dubowska W (February 2011). "Frequent hypermethylation of DAPK, RARbeta, MGMT, RASSF1A and FHIT in laryngeal squamous cell carcinomas and adjacent normal mucosa". Oral Oncol. 47 (2): 104–7. doi:10.1016/j.oraloncology.2010.11.006. PMID 21147548.
  21. Zuo C, Zhang H, Spencer HJ, Vural E, Suen JY, Schichman SA, Smoller BR, Kokoska MS, Fan CY (October 2009). "Increased microsatellite instability and epigenetic inactivation of the hMLH1 gene in head and neck squamous cell carcinoma". Otolaryngol Head Neck Surg. 141 (4): 484–90. doi:10.1016/j.otohns.2009.07.007. PMID 19786217.
  22. 1 2 Safar AM, Spencer H, Su X, Coffey M, Cooney CA, Ratnasinghe LD, Hutchins LF, Fan CY (2005). "Methylation profiling of archived non-small cell lung cancer: a promising prognostic system". Clin. Cancer Res. 11 (12): 4400–5. doi:10.1158/1078-0432.CCR-04-2378. PMID 15958624.
  23. Zou XP, Zhang B, Zhang XQ, Chen M, Cao J, Liu WJ (November 2009). "Promoter hypermethylation of multiple genes in early gastric adenocarcinoma and precancerous lesions". Hum. Pathol. 40 (11): 1534–42. doi:10.1016/j.humpath.2009.01.029. PMID 19695681.
  24. Wani M, Afroze D, Makhdoomi M, Hamid I, Wani B, Bhat G, Wani R, Wani K (2012). "Promoter methylation status of DNA repair gene (hMLH1) in gastric carcinoma patients of the Kashmir valley". Asian Pac. J. Cancer Prev. 13 (8): 4177–81. doi:10.7314/APJCP.2012.13.8.4177. PMID 23098428.
  25. Agarwal A, Polineni R, Hussein Z, Vigoda I, Bhagat TD, Bhattacharyya S, Maitra A, Verma A (2012). "Role of epigenetic alterations in the pathogenesis of Barrett's esophagus and esophageal adenocarcinoma". Int J Clin Exp Pathol. 5 (5): 382–96. PMC 3396065Freely accessible. PMID 22808291.
  26. O'Hagan HM, Mohammad HP, Baylin SB (2008). "Double strand breaks can initiate gene silencing and SIRT1-dependent onset of DNA methylation in an exogenous promoter CpG island". PLoS Genetics. 4 (8): e1000155. doi:10.1371/journal.pgen.1000155. PMC 2491723Freely accessible. PMID 18704159.
  27. Cuozzo C, Porcellini A, Angrisano T, et al. (July 2007). "DNA damage, homology-directed repair, and DNA methylation". PLoS Genetics. 3 (7): e110. doi:10.1371/journal.pgen.0030110. PMC 1913100Freely accessible. PMID 17616978.
  28. Shanbhag NM, Rafalska-Metcalf IU, Balane-Bolivar C, Janicki SM, Greenberg RA (June 2010). "ATM-dependent chromatin changes silence transcription in cis to DNA double-strand breaks". Cell. 141 (6): 970–81. doi:10.1016/j.cell.2010.04.038. PMC 2920610Freely accessible. PMID 20550933.
  29. Morano A, Angrisano T, Russo G, Landi R, Pezone A, Bartollino S, Zuchegna C, Babbio F, Bonapace IM, Allen B, Muller MT, Chiariotti L, Gottesman ME, Porcellini A, Avvedimento EV (January 2014). "Targeted DNA methylation by homology-directed repair in mammalian cells. Transcription reshapes methylation on the repaired gene". Nucleic Acids Res. 42 (2): 804–21. doi:10.1093/nar/gkt920. PMC 3902918Freely accessible. PMID 24137009.
  30. Fernandez AF, Assenov Y, Martin-Subero JI, Balint B, Siebert R, Taniguchi H, Yamamoto H, Hidalgo M, Tan AC, Galm O, Ferrer I, Sanchez-Cespedes M, Villanueva A, Carmona J, Sanchez-Mut JV, Berdasco M, Moreno V, Capella G, Monk D, Ballestar E, Ropero S, Martinez R, Sanchez-Carbayo M, Prosper F, Agirre X, Fraga MF, Graña O, Perez-Jurado L, Mora J, Puig S, Prat J, Badimon L, Puca AA, Meltzer SJ, Lengauer T, Bridgewater J, Bock C, Esteller M (2012). "A DNA methylation fingerprint of 1628 human samples". Genome Res. 22 (2): 407–19. doi:10.1101/gr.119867.110. PMC 3266047Freely accessible. PMID 21613409.
  31. Friedman, RC; Farh, KK; Burge, CB; Bartel, DP (January 2009). "Most mammalian mRNAs are conserved targets of microRNAs". Genome Res. 19 (1): 92–105. doi:10.1101/gr.082701.108. PMC 2612969Freely accessible. PMID 18955434.
  32. Krek A, Grün D, Poy MN, Wolf R, Rosenberg L, Epstein EJ, MacMenamin P, da Piedade I, Gunsalus KC, Stoffel M, Rajewsky N (2005). "Combinatorial microRNA target predictions". Nat. Genet. 37 (5): 495–500. doi:10.1038/ng1536. PMID 15806104.
  33. Vrba L, Muñoz-Rodríguez JL, Stampfer MR, Futscher BW (2013). "miRNA gene promoters are frequent targets of aberrant DNA methylation in human breast cancer". PLoS ONE. 8 (1): e54398. doi:10.1371/journal.pone.0054398. PMC 3547033Freely accessible. PMID 23342147.
  34. Li Y, Zhang Y, Li S, Lu J, Chen J, Wang Y, Li Y, Xu J, Li X (2015). "Genome-wide DNA methylome analysis reveals epigenetically dysregulated non-coding RNAs in human breast cancer". Sci Rep. 5: 8790. doi:10.1038/srep08790. PMC 4350105Freely accessible. PMID 25739977.
  35. 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 (2013). "MicroRNA-182-5p targets a network of genes involved in DNA repair". RNA. 19 (2): 230–42. doi:10.1261/rna.034926.112. PMC 3543090Freely accessible. PMID 23249749.
  36. 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 (2011). "miR-182-mediated downregulation of BRCA1 impacts DNA repair and sensitivity to PARP inhibitors". Mol. Cell. 41 (2): 210–20. doi:10.1016/j.molcel.2010.12.005. PMC 3249932Freely accessible. PMID 21195000.
  37. Suzuki H, Maruyama R, Yamamoto E, Kai M (2012). "DNA methylation and microRNA dysregulation in cancer". Mol Oncol. 6 (6): 567–78. doi:10.1016/j.molonc.2012.07.007. PMID 22902148.
  38. Suzuki H, Maruyama R, Yamamoto E, Kai M (2013). "Epigenetic alteration and microRNA dysregulation in cancer". Front Genet. 4: 258. doi:10.3389/fgene.2013.00258. PMC 3847369Freely accessible. PMID 24348513.
  39. Kaur S, Lotsari-Salomaa JE, Seppänen-Kaijansinkko R, Peltomäki P (2016). "MicroRNA Methylation in Colorectal Cancer". Adv. Exp. Med. Biol. 937: 109–22. doi:10.1007/978-3-319-42059-2_6. PMID 27573897.
  40. Majid S, Dar AA, Saini S, Shahryari V, Arora S, Zaman MS, Chang I, Yamamura S, Tanaka Y, Chiyomaru T, Deng G, Dahiya R (2013). "miRNA-34b inhibits prostate cancer through demethylation, active chromatin modifications, and AKT pathways". Clin. Cancer Res. 19 (1): 73–84. doi:10.1158/1078-0432.CCR-12-2952. PMC 3910324Freely accessible. PMID 23147995.
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