Skip to main content

Advertisement

Log in

The Role of Epigenetic Changes in Ovarian Cancer: A Review

  • Review Article
  • Published:
Indian Journal of Gynecologic Oncology Aims and scope Submit manuscript

Abstract

Ovarian cancer (OC) is a third-most lethal cancer among women after breast and cervical cancer. Epigenetics is the study of altered heritable phenotype(s), changes affecting the gene expression and activity without changes in the DNA sequence. DNA methylation, histone modifications and micro-RNA expression play a pivotal role in the development and proliferation of ovarian cancer. These epigenetic changes are stable and are affiliated with specific disease subtypes. Studies discern that these epigenetic changes can be used as potential biomarker strategy or as a therapeutic lead to diagnose and treat OC. This review highlights the role of epigenetic changes leading to ovarian cancer. Also, since these changes are located in the serum, it alleviates their chances of becoming an efficient and accurate diagnostic biomarker.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Torre LA, Trabert B, et al. Ovarian cancer statistics. CA Cancer J Clinic. 2018;68(4):284–96. https://doi.org/10.3322/caac.21456.

    Article  Google Scholar 

  2. Romero I, Bast RC Jr. Minireview: human ovarian cancer: biology, current management, and paths to personalizing therapy. Endocrinology. 2012;153(4):1593–602.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Qazi S. A coadunation of Person-centric Systems healthcare for the development of efficient diagnosis and treatment in Ovarian Cancer. J Appl Comput. 2018;3(1):1–11.

    Google Scholar 

  4. Jemal A, Bray F, et al. Global cancer statistics. CA Cancer J Clin. 2011;61(2):69–90.

    PubMed  Google Scholar 

  5. Howlader N, Noore AM, et al. Seer cancer statistics review: 1975 to 2014. Bethesda: National Cancer Institute; 2017.

    Google Scholar 

  6. Assis J, Pereira D, et al. Ovarian cancer overview: Molecular biology and its potential clinical applications Ovarian Cancer from pathogenesis to treatment. Intechopen. 2018;24:57–82.

    Google Scholar 

  7. Jones PA, Laird PW. Cancer epigenetics comes of age. Nat Genet. 1999;21(2):163–7.

    CAS  PubMed  Google Scholar 

  8. Jones PA, Baylin SB. The fundamental role of epigenetic events in cancer. Nat Rev Genet. 2002;3(6):415–28.

    CAS  PubMed  Google Scholar 

  9. Feinberg AP, Tycko B. The history of cancer epigenetics. Nat Rev Cancer. 2004;4(2):143–53.

    CAS  PubMed  Google Scholar 

  10. Balch C, Huang TH, et al. The epigenetics of ovarian cancer drug resistance and resensitization. Am J ObstetGynecol. 2004;191:1552–72.

    CAS  Google Scholar 

  11. Jones PA, Takai D. The role of DNA methylation in mammalian epigenetics. Science. 2001;293(5532):1068–70.

    CAS  PubMed  Google Scholar 

  12. Reik W, Lewis A. Co-evolution of X-chromosome inactivation and imprinting in mammals. Nat Rev Genet. 2005;6(5):403–10.

    CAS  PubMed  Google Scholar 

  13. Kacem S, Feil R. Chromatin mechanisms in genomic imprinting. Mamm Genome. 2009;20(9–10):544–56.

    CAS  PubMed  Google Scholar 

  14. Portela A, Esteller M. Epigenetic modifications and human disease. Nat Biotechnol. 2010;28(10):1057–68.

    CAS  PubMed  Google Scholar 

  15. Abdollahi A, Pisarcik D, et al. LOT1 (PLAGL1/ZAC1), the candidate tumor suppressor gene at chromosome 6q24-25, is epigenetically regulated in cancer. J Biol Chem. 2003;278:6041–9.

    CAS  PubMed  Google Scholar 

  16. Jones PA, Baylin SB. The epigenomics of cancer. Cell. 2007;128(4):683–92.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Bernstein BE, Meissner A, Lander ES. The mammalian epigenome. Cell. 2007;128:669–81.

    CAS  PubMed  Google Scholar 

  18. Lopez J, Percharde M, et al. The context and potential of epigenetics in oncology. Br J Cancer. 2009;100:571–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Schickel R, Boyerinas B, et al. MicroRNAs: key players in the immune system, differentiation, tumorigenesis and cell death. Oncogene. 2008;27:5959–74.

    CAS  PubMed  Google Scholar 

  20. Iorio MV, Visone R, et al. MicroRNA signatures in human ovarian cancer. Cancer Res. 2007;67:8699–707.

    CAS  PubMed  Google Scholar 

  21. Widschwendter M, Jiang G, et al. DNA hypomethylation and ovarian cancer biology. Cancer Res. 2004;64:4472–80.

    CAS  PubMed  Google Scholar 

  22. Bird AP, Wolffe AP. Methylation-induced repression–belts, braces, and chromatin. Cell. 1999;99(5):451–4.

    CAS  PubMed  Google Scholar 

  23. Hendrich B, Bird A. Mammalian methyltransferases and methyl-CpG-binding domains: proteins involved in DNA methylation. Curr Top Microbiol Immunol. 2000;249:55–74.

    CAS  PubMed  Google Scholar 

  24. Bird A. DNA methylation patterns and epigenetic memory. Genes Dev. 2002;16(1):6–21.

    CAS  PubMed  Google Scholar 

  25. Esteller M. Epigenetic gene silencing in cancer: the DNA hypermethylome. Hum Mol Genet. 2007;16(1):R50–9.

    CAS  PubMed  Google Scholar 

  26. Lopez-Serra L, Esteller M. Proteins that bind methylated DNA and human cancer: reading the wrong words. Br J Cancer. 2008;98(12):1881–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Thomson JP, Skene PJ, et al. CpG islands influence chromatin structure via the CpG-binding protein Cfp1. Nature. 2010;464(7291):1082–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Caslini C, Capo-chichi CD, et al. Histone modifications silence the GATA transcription factor genes in ovarian cancer. Oncogene. 2006;25:5446–61.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Valls E, Sa´nchez-Molina S, Martínez-Balba MA. Role of histone modifications in marking and activating genes through mitosis. J Biol Chem. 2005;280:42592–600.

    CAS  PubMed  Google Scholar 

  30. Balch C, Fang F, et al. Minireview: epigenetic changes in ovarian cancer. Endocrinology. 2009;150(9):4003–11.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Staub J, Chien J, et al. Epigenetic silencing of HSulf-1 in ovarian cancer: implications in chemoresistance. Oncogene. 2007;26:4969–78.

    CAS  PubMed  Google Scholar 

  32. Milde-Langosch K, Ocon E, et al. p16/MTS1 inactivation in ovarian carcinomas: high frequency of reduced protein expression associated with hyper-methylation or mutation in endometrioid and mucinous tumors. Int J Cancer. 1998;79:61–5.

    CAS  PubMed  Google Scholar 

  33. Feng W, Marquez RT, et al. Imprinted tumor suppressor genes ARHI and PEG3 are the most frequently down-regulated in human ovarian cancers by loss of heterozygosity and promoter methylation. Cancer. 2008;112:1489–502.

    CAS  PubMed  Google Scholar 

  34. Cvetkovic D, Pisarcik D, et al. Altered expression and loss of heterozygosity of the LOT1 gene in ovarian cancer. Gynecol Oncol. 2004;95:449–55.

    CAS  PubMed  Google Scholar 

  35. Pruitt K, Ulku AS, et al. Ras-mediated loss of the pro-apoptotic response protein Par-4 is mediated by DNA hypermethylation through Raf-independent and Raf-dependent signaling cascades in epithelial cells. J Biol Chem. 2005;280:23363–70.

    CAS  PubMed  Google Scholar 

  36. Terasawa K, Sagae S, et al. Epigenetic inactivation of TMS1/ASC in ovarian cancer. Clin Cancer Res. 2004;10:2000–6.

    CAS  PubMed  Google Scholar 

  37. Yuecheng Y, Hongmei L, Xiaoyan X. Clinical evaluation of E-cadherin expression and its regulation mechanism in epithelial ovarian cancer. Clin Exp Metastasis. 2006;23:65–74.

    PubMed  Google Scholar 

  38. Strathdee G, Vass JK, et al. Demethylation of the MCJ gene in stage III/IV epithelial ovarian cancer and response to chemotherapy. Gynecol Oncol. 2005;97:898–903.

    CAS  PubMed  Google Scholar 

  39. Czekierdowski A, Czekierdowska S, et al. The role of CpG islands hypomethylation and abnormal expression of neuronal protein synuclein-gamma (SNCG) in ovarian cancer. Neuro Endocrinol Lett. 2006;27:381–6.

    CAS  PubMed  Google Scholar 

  40. Woloszynska-Read A, James SR, et al. DNA methylation-dependent regulation of BORIS/CTCFL expression in ovarian cancer. Cancer Immun. 2007;7:21.

    PubMed  PubMed Central  Google Scholar 

  41. Murphy SK, Huang Z, et al. Frequent IGF2/H19 domain epigenetic alterations and elevated IGF2 expression in epithelial ovarian cancer. Mol Cancer Res. 2006;4:283–92.

    CAS  PubMed  Google Scholar 

  42. Litkouhi B, Kwong J, et al. Claudin-4 overexpression in epithelial ovarian cancer is associated with hypomethylation and is a potential target for modulation of tight junction barrier function using a C-terminal fragment of Clostridium perfringens enterotoxin. Neoplasia. 2007;9:304–14.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Sharma A, Albahrani M, et al. Epigenetic activation of POTE genes in ovarian cancer. Epigenetics. 2019;14(2):185–97.

    PubMed  PubMed Central  Google Scholar 

  44. Yang H, Kong W, et al. MicroRNA expression profiling in human ovarian cancer: miR-214 induces cell survival and cisplatin resistance by targeting PTEN. Cancer Res. 2008;68:425–33.

    CAS  PubMed  Google Scholar 

  45. Press JZ, De Luca A, et al. Ovarian carcinomas with genetic and epigenetic BRCA1 loss have distinct molecular abnormalities. BMC Cancer. 2008;8:17.

    PubMed  PubMed Central  Google Scholar 

  46. Ibanez I, de Caceres I, Battagli C, et al. Tumor cell-specific BRCA1 and RASSF1A hypermethylation in serum, plasma, and peritoneal fluid from ovarian cancer patients. Cancer Res. 2004;64:6476–81.

    Google Scholar 

  47. Petrocca F, Iliopoulos D, et al. Alterations of the tumor suppressor gene ARLTS1 in ovarian cancer. Cancer Res. 2006;66:10287–91.

    CAS  PubMed  Google Scholar 

  48. Kikuchi R, Tsuda H, et al. Promoter hypermethylation contributes to frequent inactivation of a putative conditional tumor suppressor gene connective tissue growth factor in ovarian cancer. Cancer Res. 2007;67:7095–105.

    CAS  PubMed  Google Scholar 

  49. Socha MJ, Said N, et al. Aberrant promoter methylation of sparc in ovarian cancer. Neoplasia. 2009;11:126–35.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Yanaihara N, Nishioka M, et al. Reduced expression of MYO18B, a candidate tumor-suppressor gene on chromosome arm 22q, in ovarian cancer. Int J Cancer. 2004;112:150–4.

    CAS  PubMed  Google Scholar 

  51. Schondorf T, Ebert MP, et al. Hypermethylation of the PTEN gene in ovarian cancer cell lines. Cancer Lett. 2004;207:215–20.

    CAS  PubMed  Google Scholar 

  52. Fiegl H, Windbichler G, et al. HOXA11 DNA methylation: a novel prognostic biomarker in ovarian cancer. Int J Cancer. 2008;123:725–9.

    CAS  PubMed  Google Scholar 

  53. Chan MW, Huang YW, et al. Aberrant transforming growth factor 1 signaling and SMAD4 nuclear translocation confer epigenetic repression of ADAM19 in ovarian cancer. Neoplasia. 2008;10:908–19.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Abbosh PH, Montgomery JS, et al. Dominant-negative histone H3 lysine 27 mutant derepresses silenced tumor suppressor genes and reverses the drug-resistant phenotype in cancer cells. Cancer Res. 2006;66:5582–91.

    CAS  PubMed  Google Scholar 

  55. Ye W, Lv Q, et al. The effect of central loops in miRNA:MRE duplexes on the efficiency of miRNA-mediated gene regulation. PLoS ONE. 2008;3:e1719.

    PubMed  PubMed Central  Google Scholar 

  56. Xia L, Zhang D, et al. miR-15b and miR-16 modulate multidrug resistance by targeting BCL2 in human gastric cancer cells. Int J Cancer. 2008;123:372–9.

    CAS  PubMed  Google Scholar 

  57. Bera TK, Fleur AS, et al. POTE paralogs are induced and differentially expressed in many cancers. Cancer Res. 2006;66(1):52–6.

    CAS  PubMed  Google Scholar 

  58. Lee Y, Ise T, et al. Evolution and expression of chimeric POTE-actin genes in the human genome. Proc Natl Acad Sci. 2006;103(47):17885–90.

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Barger CJ, Zhang W, et al. Expression of the POTE gene family in human ovarian cancer. Sci Rep. 2018;8(1):1–3.

    CAS  Google Scholar 

  60. Chen CP, Wang KG, et al. Detection of mosaic 15q11.1-q11.2 deletion encompassing NBEAP1 and POTEB in a fetus with diffuse lymphangiomatosis. Taiwan J ObstetGyne. 2017;56:230–3.

    Google Scholar 

  61. Wang Q, Li X, Ren S, et al. Serum levels of the cancer-testis antigen POTEE and its clinical significance in non-small-cell lung cancer. PLoS ONE. 2015;10:e0122792.

    PubMed  PubMed Central  Google Scholar 

  62. Liu X, Tang H, et al. POTEH hypomethylation, a new epigenetic biomarker for glioma prognosis. Brain Res. 2011;1391:125–31.

    CAS  PubMed  Google Scholar 

  63. Li Y, Guan XY, Wang L. POTEG is a Prognostic Biomarker for ESCC. J Mol Cancer. 2018;1(3):20–1.

    Google Scholar 

  64. Singh A, Gupta S, Sachan M. Epigenetic Biomarkers in the Management of Ovarian Cancer: Current Prospectives. Front Cell Develop Biol. 2019;7:182.

    Google Scholar 

  65. Gloss BS, Patterson KI, et al. Integrative genome-wide expression and promoter DNA methylation profiling identifies a potential novel panel of ovarian cancer epigenetic biomarkers. Cancer Lett. 2012;318:76–85.

    CAS  PubMed  Google Scholar 

  66. Kaur M, Singh A, et al. Development of a multiplex MethyLight assay for the detection of DAPK1 and SOX1 methylation in epithelial ovarian cancer in a north Indian population. Genes Genet Syst. 2016;91:175–81.

    CAS  PubMed  Google Scholar 

  67. Kang S, Dong SM, Park NH. Frequent promoter hypermethylation of TGFBI in epithelial ovarian cancer. Gynecol Oncol. 2010;118:58–63.

    CAS  PubMed  Google Scholar 

  68. Cai L, Abe M, et al. Identification of PRTFDC1 silencing and aberrant promoter methylation of GPR150, ITGA8 and HOXD11 in ovarian cancers. Life Sci. 2007;80:1458–65.

    CAS  PubMed  Google Scholar 

  69. Buchholtz ML, Brüning A, et al. Epigenetic silencing of the LDOC1 tumor suppressor gene in ovarian cancer cells. Arch Gynecol Obstet. 2014;290:149–54.

    CAS  PubMed  Google Scholar 

  70. Rattanapan Y, Korkiatsakul V, et al. EGFL7 and RASSF1 promoter hypermethylation in epithelial ovarian cancer. Cancer Genet. 2018;224–225:37–40.

    PubMed  Google Scholar 

  71. Baranova I, Kovarikova H, et al. Aberrant methylation of PCDH17 gene in high-grade serous ovarian carcinoma. Cancer Biomark. 2018;23:125–33.

    CAS  PubMed  Google Scholar 

  72. Gupta A, Godwin AK, et al. Hypomethylation of the synuclein gamma gene CpG island promotes its aberrant expression in breast carcinoma and ovarian carcinoma. Cancer Res. 2003;63:664–73.

    CAS  PubMed  Google Scholar 

  73. Rose SL, Fitzgerald MP, et al. Epigenetic regulation of maspin expression in human ovarian carcinoma cells. Gynecol Oncol. 2006;102:319–24.

    CAS  PubMed  Google Scholar 

  74. Choi YL, Kim J, et al. Expression profile of tight junction protein claudin 3 and claudin 4 in ovarian serous adenocarcinoma with prognostic correlation. Histol Histopathol. 2007;22:1185–95.

    CAS  PubMed  Google Scholar 

  75. Honda H, Pazin MJ, et al. Regulation of the CLDN3 gene in ovarian cancer cells. Cancer Biol Ther. 2007;6:1733–42.

    CAS  PubMed  Google Scholar 

  76. Akahira J, Sugihashi Y, et al. Decreased expression of 14-3-3 sigma is associated with advanced disease in human epithelial ovarian cancer: its correlation with aberrant DNA methylation. Clin Cancer Res Off J Am Assoc Cancer Res. 2004;10:2687–93.

    CAS  Google Scholar 

  77. Barton CA, Hacker NF, et al. DNA methylation changes in ovarian cancer: implications for early diagnosis, prognosis and treatment. Gynecol Oncol. 2008;109(1):129–39.

    CAS  PubMed  Google Scholar 

  78. Sawada K, Mitra AK, et al. Loss of E-cadherin promotes ovarian cancer metastasis via alpha 5-integrin, which is a therapeutic target. Cancer Res. 2008;68(7):2329–39.

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Barton CA, Gloss BS, et al. Collagen and calcium-binding EGF domains 1 is frequently inactivated in ovarian cancer by aberrant promoter hypermethylation and modulates cell migration and survival. Br J Cancer. 2010;102(1):87–96.

    CAS  PubMed  Google Scholar 

  80. Barbolina MV, Adley BP, et al. Downregulation of connective tissue growth factor by three-dimensional matrix enhances ovarian carcinoma cell invasion. Int J Cancer. 2009;125(4):816–25.

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Huang YW, Jansen RA, et al. Identification of candidate epigenetic biomarkers for ovarian cancer detection. Oncol Rep. 2009;22:853–61.

    CAS  PubMed  Google Scholar 

  82. Wu Q, Lothe RA, et al. DNA methylation profiling of ovarian carcinomas and their in vitro models identifies HOXA9, HOXB5, SCGB3A1, and CRABP1 as novel targets. Mol Cancer. 2007;6:45.

    PubMed  PubMed Central  Google Scholar 

  83. Feng Q, Deftereos G, et al. DNA hypermethylation, Her-2/neu overexpression and p53 mutations in ovarian carcinoma. Gynecol Oncol. 2008;111:320–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Bhasin M, Zhang H, et al. Prediction of methylated CpGs in DNA sequences using a support vector machine. FEBS Lett. 2005;579:4302–8.

    CAS  PubMed  Google Scholar 

  85. Lu L, Lin K, et al. Predicting DNA methylation status using word composition. J Biomed Sci Eng. 2010;3:672–6.

    CAS  Google Scholar 

  86. Ali I, Seker H, Detailed methylation prediction of CpG islands on human chromosome 21. 10th WSEAS International Conference on Mathematics and Computers. In: Biology and Chemistry; 2009. pp. 147–52.

  87. Fan S, Zhang M, Zhang X. Histone methylation marks play important roles in predicting the methylation status of CpG islands. BiochemBiophys Res Commun. 2008;374:559–64.

    CAS  Google Scholar 

  88. Previti C, Harari O, et al. Profile analysis and prediction of tissuespecific CpG island methylation classes. BMC Bioinformatics. 2009;10:116.

    PubMed  PubMed Central  Google Scholar 

  89. Zhang W, Spector TD, et al. Predicting genomewide DNA methylation using methylation marks, genomic position, and DNA regulatory elements. Genome Biol. 2015;16:14.

    PubMed  PubMed Central  Google Scholar 

  90. Cava C, Bertoli G, Castiglioni I. Integrating genetics and epigenetics in breast cancer: biological insights, experimental, computational methods and therapeutic potential. BMC Syst Biol. 2015;9(1):1–36.

    Google Scholar 

  91. Du P, Bourgon R, MethyAnalysis: DNA methylation data analysis and visualization. R package version 1.10.0.; (2014).

  92. Barfield RT, Kilaru V, et al. CpGassoc: an R function for analysis of DNA methylation microarray data. Bioinformatics. 2012;9:1280–1.

    Google Scholar 

  93. Assenov Y, Mueller F, et al. Compehensive analysis of DNA Methylation Data with RnBeads. Nat Methods. 2014;11:1138–40.

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Wang D, Yan L, et al. IMA: an R package for high-throughput analysis of Illumina’s 450K Infinium methylation data. Bioinformatics. 2012;5:729–30.

    Google Scholar 

  95. Price EM, Cotton AM, et al. Additional annotation enhances potential for biologically-relevant analysis of the illuminainfinium humanmethylation450 beadchip array. Epigenetics Chromatin. 2013;1:4.

    Google Scholar 

  96. Friedman J, Fisher NI. Statistics Comput. 1999;9(2):123–43.

    Google Scholar 

  97. Jaffe AE, Murakami P, et al. Bump hunting to identify differentially methylated regions in epigenetic epidemiology studies. Int J Epidemiol. 2012;1:200–9.

    Google Scholar 

  98. Cortez AJ, Tudrej P, et al. Advances in ovarian cancer therapy. Cancer Chemother Pharmacol. 2018;81(1):17–38.

    CAS  PubMed  Google Scholar 

  99. Bera TK, Huynh N, et al. Five POTE paralogs and their splice variants are expressed in human prostate and encode proteins of different lengths. Gene. 2004;337:45–53.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

SQ was supported by DST-INSPIRE fellowship provided by the Department of Science and Technology, Govt. of India.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Khalid Raza.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Qazi, S., Sharma, A. & Raza, K. The Role of Epigenetic Changes in Ovarian Cancer: A Review. Indian J Gynecol Oncolog 19, 27 (2021). https://doi.org/10.1007/s40944-021-00505-z

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s40944-021-00505-z

Keywords

Navigation