Epigenetics of colorectal cancer: biomarker and therapeutic potential

Abstract

Colorectal cancer (CRC), a leading cause of cancer-related death worldwide, evolves as a result of the stepwise accumulation of a series of genetic and epigenetic alterations in the normal colonic epithelium, leading to the development of colorectal adenomas and invasive adenocarcinomas. Although genetic alterations have a major role in a subset of CRCs, the pathophysiological contribution of epigenetic aberrations in this malignancy has attracted considerable attention. Data from the past couple of decades has unequivocally illustrated that epigenetic marks are important molecular hallmarks of cancer, as they occur very early in disease pathogenesis, involve virtually all key cancer-associated pathways and, most importantly, can be exploited as clinically relevant disease biomarkers for diagnosis, prognostication and prediction of treatment response. In this Review, we summarize the current knowledge on the best-studied epigenetic modifications in CRC, including DNA methylation and histone modifications, as well as the role of non-coding RNAs as epigenetic regulators. We focus on the emerging potential for the bench-to-bedside translation of some of these epigenetic alterations into clinical practice and discuss the burgeoning evidence supporting the potential of emerging epigenetic therapies in CRC as we usher in the era of precision medicine.

Key points

  • Epigenetic changes, notably DNA methylation and histone modifications, have key pathophysiological roles in the initiation and progression of colorectal cancer (CRC).

  • Non-coding RNAs (ncRNAs) such as microRNAs (miRNAs) and long ncRNAs are also important regulators of gene expression and are implicated in many CRC-related pathways.

  • Epigenetic changes and altered expression of ncRNAs can be exploited as biomarkers for the diagnosis, prognostication and prediction of treatment response in CRC.

  • Biomarkers based on DNA methylation have been commercialized, and some have already found their way into clinical practice and guidelines in CRC.

  • miRNAs are the most promising and fastest-growing group of potential future biomarkers for CRC; their implications in clinical practice are expected within the next decade.

  • Epigenetic changes are potentially reversible and are attractive targets for future cancer treatments; preclinical and phase I/II studies have proven the utility of epigenetic modifiers.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Principles of epigenetics.
Fig. 2: Role of miRNAs and lncRNAs in CRC.
Fig. 3: Epigenetic biomarkers in CRC.

References

  1. 1.

    Bray, F. et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 68, 394–424 (2018).

    PubMed  Google Scholar 

  2. 2.

    European Cancer Information System. Measuring cancer burden and its time trends across Europe. ECIS https://ecis.jrc.ec.europa.eu (2019).

  3. 3.

    Siegel, R. L., Miller, K. D. & Jemal, A. Cancer statistics, 2019. CA Cancer J. Clin. 69, 7–34 (2019).

    PubMed  Google Scholar 

  4. 4.

    Goel, A. & Boland, C. R. Epigenetics of colorectal cancer. Gastroenterology 143, 1442–1460.e1 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. 5.

    Dienstmann, R. et al. Consensus molecular subtypes and the evolution of precision medicine in colorectal cancer. Nat. Rev. Cancer 17, 79–92 (2017).

    CAS  PubMed  Google Scholar 

  6. 6.

    Herman, J. G. et al. Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma. Proc. Natl Acad. Sci. USA 95, 6870–6875 (1998).

    CAS  PubMed  Google Scholar 

  7. 7.

    Suter, C. M., Martin, D. I. & Ward, R. L. Hypomethylation of L1 retrotransposons in colorectal cancer and adjacent normal tissue. Int. J. Colorectal Dis. 19, 95–101 (2004).

    PubMed  Google Scholar 

  8. 8.

    Strubberg, A. M. & Madison, B. B. MicroRNAs in the etiology of colorectal cancer: pathways and clinical implications. Dis. Model. Mech. 10, 197–214 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Chen, X. et al. Role of miR-143 targeting KRAS in colorectal tumorigenesis. Oncogene 28, 1385–1392 (2009).

    CAS  PubMed  Google Scholar 

  10. 10.

    Kanai, Y. & Hirohashi, S. Alterations of DNA methylation associated with abnormalities of DNA methyltransferases in human cancers during transition from a precancerous to a malignant state. Carcinogenesis 28, 2434–2442 (2007).

    CAS  PubMed  Google Scholar 

  11. 11.

    Gardiner-Garden, M. & Frommer, M. CpG islands in vertebrate genomes. J. Mol. Biol. 196, 261–282 (1987).

    CAS  PubMed  Google Scholar 

  12. 12.

    Ng, J. & Yu, J. Promoter hypermethylation of tumour suppressor genes as potential biomarkers in colorectal cancer. Int. J. Mol. Sci. 16, 2472–2496 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Lao, V. V. & Grady, W. M. Epigenetics and colorectal cancer. Nat. Rev. Gastroenterol. Hepatol. 8, 686–700 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Okugawa, Y., Grady, W. M. & Goel, A. Epigenetic alterations in colorectal cancer: emerging biomarkers. Gastroenterology 149, 1204–1225.e12 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Bihl, M. P., Foerster, A., Lugli, A. & Zlobec, I. Characterization of CDKN2A(p16) methylation and impact in colorectal cancer: systematic analysis using pyrosequencing. J. Transl. Med. 10, 173 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Esteller, M. et al. K-ras and p16 aberrations confer poor prognosis in human colorectal cancer. J. Clin. Oncol. 19, 299–304 (2001).

    CAS  PubMed  Google Scholar 

  17. 17.

    Esteller, M. et al. Hypermethylation-associated inactivation of p14(ARF) is independent of p16(INK4a) methylation and p53 mutational status. Cancer Res. 60, 129–133 (2000).

    CAS  PubMed  Google Scholar 

  18. 18.

    Cunningham, J. M. et al. Hypermethylation of the hMLH1 promoter in colon cancer with microsatellite instability. Cancer Res. 58, 3455–3460 (1998).

    CAS  PubMed  Google Scholar 

  19. 19.

    Liang, T.-J. et al. APC hypermethylation for early diagnosis of colorectal cancer: a meta-analysis and literature review. Oncotarget 8, 46468–46479 (2017).

    PubMed  PubMed Central  Google Scholar 

  20. 20.

    Yang, X. et al. Gene body methylation can alter gene expression and is a therapeutic target in cancer. Cancer Cell 26, 577–590 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Sunami, E., de Maat, M., Vu, A., Turner, R. R. & Hoon, D. S. B. LINE-1 hypomethylation during primary colon cancer progression. PLOS ONE 6, e18884 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Nagai, Y. et al. LINE-1 hypomethylation status of circulating cell-free DNA in plasma as a biomarker for colorectal cancer. Oncotarget 8, 11906–11916 (2017).

    PubMed  PubMed Central  Google Scholar 

  23. 23.

    Hur, K. et al. Hypomethylation of long interspersed nuclear element-1 (LINE-1) leads to activation of proto-oncogenes in human colorectal cancer metastasis. Gut 63, 635–646 (2014).

    CAS  PubMed  Google Scholar 

  24. 24.

    Milicic, A. et al. Ectopic expression of P-cadherin correlates with promoter hypomethylation early in colorectal carcinogenesis and enhanced intestinal crypt fission in vivo. Cancer Res. 68, 7760–7768 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Pérez, R. F., Tejedor, J. R., Bayón, G. F., Fernández, A. F. & Fraga, M. F. Distinct chromatin signatures of DNA hypomethylation in aging and cancer. Aging Cell 17, e12744 (2018).

    PubMed  PubMed Central  Google Scholar 

  26. 26.

    Baba, Y. et al. Hypomethylation of the IGF2 DMR in colorectal tumors, detected by bisulfite pyrosequencing, is associated with poor prognosis. Gastroenterology 139, 1855–1864 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Luo, J., Li, Y.-N., Wang, F., Zhang, W.-M. & Geng, X. S-adenosylmethionine inhibits the growth of cancer cells by reversing the hypomethylation status of c-myc and H-ras in human gastric cancer and colon cancer. Int. J. Biol. Sci. 6, 784–795 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Antelo, M. et al. A high degree of LINE-1 hypomethylation is a unique feature of early-onset colorectal cancer. PLOS ONE 7, e45357 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Baba, Y. et al. Long interspersed element-1 methylation level as a prognostic biomarker in gastrointestinal cancers. Digestion 97, 26–30 (2018).

    CAS  PubMed  Google Scholar 

  30. 30.

    Ogino, S. et al. LINE-1 hypomethylation is inversely associated with microsatellite instability and CpG island methylator phenotype in colorectal cancer. Int. J. Cancer 122, 2767–2773 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Chi, P., Allis, C. D. & Wang, G. G. Covalent histone modifications–miswritten, misinterpreted and mis-erased in human cancers. Nat. Rev. Cancer 10, 457–469 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Hanigan, C. L. et al. An inactivating mutation in HDAC2 leads to dysregulation of apoptosis mediated by APAF1. Gastroenterology 135, 1654–1664.e2 (2008).

    CAS  PubMed  Google Scholar 

  33. 33.

    Gargalionis, A. N., Piperi, C., Adamopoulos, C. & Papavassiliou, A. G. Histone modifications as a pathogenic mechanism of colorectal tumorigenesis. Int. J. Biochem. Cell Biol. 44, 1276–1289 (2012).

    CAS  PubMed  Google Scholar 

  34. 34.

    Struhl, K. Histone acetylation and transcriptional regulatory mechanisms. Genes Dev. 12, 599–606 (1998).

    CAS  PubMed  Google Scholar 

  35. 35.

    Audia, J. E. & Campbell, R. M. Histone modifications and cancer. Cold Spring Harb. Perspect. Biol. 8, a019521 (2016).

    PubMed  PubMed Central  Google Scholar 

  36. 36.

    Vaish, V., Khare, T., Verma, M. & Khare, S. in Cancer Epigenetics. Methods in Molecular Biology (Methods and Protocols) Vol. 1238 (ed. Verma, M.) 771–782 (Humana, 2015).

  37. 37.

    Huang, T. et al. Targeting histone methylation for colorectal cancer. Therap. Adv. Gastroenterol. 10, 114–131 (2017).

    CAS  PubMed  Google Scholar 

  38. 38.

    Salz, T. et al. hSETD1A regulates Wnt target genes and controls tumor growth of colorectal cancer cells. Cancer Res. 74, 775–786 (2014).

    CAS  PubMed  Google Scholar 

  39. 39.

    Greer, E. L. & Shi, Y. Histone methylation: a dynamic mark in health, disease and inheritance. Nat. Rev. Genet. 13, 343–357 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 40.

    Esteller, M. Non-coding RNAs in human disease. Nat. Rev. Genet. 12, 861–874 (2011).

    CAS  PubMed  Google Scholar 

  41. 41.

    Kita, Y. et al. Noncoding RNA and colorectal cancer: its epigenetic role. J. Hum. Genet. 62, 41–47 (2017).

    CAS  PubMed  Google Scholar 

  42. 42.

    Hombach, S. & Kretz, M. Non-coding RNAs: classification, biology and functioning. Adv. Exp. Med. Biol. 937, 3–17 (2016).

    CAS  PubMed  Google Scholar 

  43. 43.

    Croce, C. M. Causes and consequences of microRNA dysregulation in cancer. Nat. Rev. Genet. 10, 704–714 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44.

    Lujambio, A. et al. A microRNA DNA methylation signature for human cancer metastasis. Proc. Natl Acad. Sci. USA 105, 13556–13561 (2008).

    CAS  PubMed  Google Scholar 

  45. 45.

    Ma, Y. et al. Candidate microRNA biomarkers in human colorectal cancer: systematic review profiling studies and experimental validation. Int. J. Cancer 130, 2077–2087 (2012).

    CAS  PubMed  Google Scholar 

  46. 46.

    Svoronos, A. A., Engelman, D. M. & Slack, F. J. OncomiR or tumor suppressor? The duplicity of microRNAs in cancer. Cancer Res. 76, 3666–3670 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 47.

    Guttman, M. & Rinn, J. L. Modular regulatory principles of large non-coding RNAs. Nature 482, 339–346 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. 48.

    Yang, Y., Du, Y., Liu, X. & Cho, W. C. Involvement of non-coding RNAs in the signaling pathways of colorectal cancer. Adv. Exp. Med. Biol. 937, 19–51 (2016).

    CAS  PubMed  Google Scholar 

  49. 49.

    Luo, J. et al. Long non-coding RNAs: a rising biotarget in colorectal cancer. Oncotarget 8, 22187–22202 (2017).

    PubMed  PubMed Central  Google Scholar 

  50. 50.

    Kogo, R. et al. Long noncoding RNA HOTAIR regulates polycomb-dependent chromatin modification and is associated with poor prognosis in colorectal cancers. Cancer Res. 71, 6320–6326 (2011).

    CAS  PubMed  Google Scholar 

  51. 51.

    Luo, Z.-F. et al. Clinical significance of HOTAIR expression in colon cancer. World J. Gastroenterol. 22, 5254–5259 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52.

    Wu, Z.-H. et al. Long non-coding RNA HOTAIR is a powerful predictor of metastasis and poor prognosis and is associated with epithelial-mesenchymal transition in colon cancer. Oncol. Rep. 32, 395–402 (2014).

    CAS  PubMed  Google Scholar 

  53. 53.

    Schwarzenbach, H. Biological and clinical relevance of H19 in colorectal cancer patients. EbioMedicine 13, 9–10 (2016).

    PubMed  PubMed Central  Google Scholar 

  54. 54.

    Bai, J. et al. Integrating analysis reveals microRNA-mediated pathway crosstalk among Crohn’s disease, ulcerative colitis and colorectal cancer. Mol. Biosyst. 10, 2317–2328 (2014).

    CAS  PubMed  Google Scholar 

  55. 55.

    Goel, A. et al. Characterization of sporadic colon cancer by patterns of genomic instability. Cancer Res. 63, 1608–1614 (2003).

    CAS  PubMed  Google Scholar 

  56. 56.

    Geigl, J. B., Obenauf, A. C., Schwarzbraun, T. & Speicher, M. R. Defining ‘chromosomal instability’. Trends Genet. 24, 64–69 (2008).

    CAS  PubMed  Google Scholar 

  57. 57.

    Fearon, E. R. & Vogelstein, B. A genetic model for colorectal tumorigenesis. Cell 61, 759–767 (1990).

    CAS  PubMed  Google Scholar 

  58. 58.

    Lynch, H. T., Lynch, J. F., Lynch, P. M. & Attard, T. Hereditary colorectal cancer syndromes: molecular genetics, genetic counseling, diagnosis and management. Fam. Cancer 7, 27–39 (2008).

    CAS  PubMed  Google Scholar 

  59. 59.

    Boland, C. R. & Goel, A. Microsatellite instability in colorectal cancer. Gastroenterology 138, 2073–2087.e3 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. 60.

    Pussila, M. et al. Mlh1 deficiency in normal mouse colon mucosa associates with chromosomally unstable colon cancer. Carcinogenesis 39, 788–797 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. 61.

    Haraldsdottir, S. et al. Colon and endometrial cancers with mismatch repair deficiency can arise from somatic, rather than germline, mutations. Gastroenterology 147, 1308–1316.e1 (2014).

    PubMed  PubMed Central  Google Scholar 

  62. 62.

    Popat, S., Hubner, R. & Houlston, R. S. Systematic review of microsatellite instability and colorectal cancer prognosis. J. Clin. Oncol. 23, 609–618 (2005).

    CAS  PubMed  Google Scholar 

  63. 63.

    Des Guetz, G. et al. Does microsatellite instability predict the efficacy of adjuvant chemotherapy in colorectal cancer? A systematic review with meta-analysis. Eur. J. Cancer 45, 1890–1896 (2009).

    CAS  PubMed  Google Scholar 

  64. 64.

    Weisenberger, D. J. et al. CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer. Nat. Genet. 38, 787–793 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. 65.

    Toyota, M. et al. CpG island methylator phenotype in colorectal cancer. Proc. Natl Acad. Sci. USA 96, 8681–8686 (1999).

    CAS  Google Scholar 

  66. 66.

    Weisenberger, D. J. et al. Association of the colorectal CpG island methylator phenotype with molecular features, risk factors, and family history. Cancer Epidemiol. Biomark. Prev. 24, 512–519 (2015).

    CAS  Google Scholar 

  67. 67.

    Jia, M., Gao, X., Zhang, Y., Hoffmeister, M. & Brenner, H. Different definitions of CpG island methylator phenotype and outcomes of colorectal cancer: a systematic review. Clin. Epigenetics 8, 1–14 (2016).

    Google Scholar 

  68. 68.

    Guinney, J. et al. The consensus molecular subtypes of colorectal cancer. Nat. Med. 21, 1350–1356 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. 69.

    Bilgin, B., Sendur, M. A. N., Bülent Akıncı, M., Şener Dede, D. & Yalçın, B. Targeting the PD-1 pathway: a new hope for gastrointestinal cancers. Curr. Med. Res. Opin. 33, 749–759 (2017).

    CAS  PubMed  Google Scholar 

  70. 70.

    Le, D. T. et al. PD-1 blockade in tumors with mismatch-repair deficiency. N. Engl. J. Med. 372, 2509–2520 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. 71.

    Le, D. T. et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science 357, 409–413 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. 72.

    Fessler, E. et al. TGFβ signaling directs serrated adenomas to the mesenchymal colorectal cancer subtype. EMBO Mol. Med. 8, 745–760 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. 73.

    Akao, Y. et al. Role of anti-oncomirs miR-143 and -145 in human colorectal tumors. Cancer Gene Ther. 17, 398–408 (2010).

    CAS  PubMed  Google Scholar 

  74. 74.

    Akao, Y. et al. Impairment of K-Ras signaling networks and increased efficacy of epidermal growth factor receptor inhibitors by a novel synthetic miR-143. Cancer Sci. 109, 1455–1467 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. 75.

    Fei, B., Wang, X. & Fang, X. MicroRNA-143 replenishment re-sensitizes colorectal cancer cells harboring mutant, but not wild-type, KRAS to paclitaxel treatment. Tumour Biol. 37, 5829–5835 (2016).

    CAS  PubMed  Google Scholar 

  76. 76.

    Gao, J. et al. miR-34a-5p suppresses colorectal cancer metastasis and predicts recurrence in patients with stage II/III colorectal cancer. Oncogene 34, 4142–4152 (2015).

    CAS  PubMed  Google Scholar 

  77. 77.

    Sun, C. et al. miR-34a mediates oxaliplatin resistance of colorectal cancer cells by inhibiting macroautophagy via transforming growth factor-β/Smad4 pathway. World J. Gastroenterol. 23, 1816–1827 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. 78.

    Rokavec, M. et al. IL-6R/STAT3/miR-34a feedback loop promotes EMT-mediated colorectal cancer invasion and metastasis. J. Clin. Invest. 124, 1853–1867 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. 79.

    Aherne, S. T. et al. Circulating miRNAs miR-34a and miR-150 associated with colorectal cancer progression. BMC Cancer 15, 329 (2015).

    PubMed  PubMed Central  Google Scholar 

  80. 80.

    Hiyoshi, Y. et al. Increased microRNA-34b and -34c predominantly expressed in stromal tissues is associated with poor prognosis in human colon cancer. PLOS ONE 10, e0124899 (2015).

    PubMed  PubMed Central  Google Scholar 

  81. 81.

    Wang, M. et al. The quantitative analysis by stem-loop real-time PCR revealed the microRNA-34a, microRNA-155 and microRNA-200c overexpression in human colorectal cancer. Med. Oncol. 29, 3113–3118 (2012).

    CAS  PubMed  Google Scholar 

  82. 82.

    Wu, Y. et al. MicroRNA-21 (Mir-21) promotes cell growth and invasion by repressing tumor suppressor PTEN in colorectal cancer. Cell. Physiol. Biochem. 43, 945–958 (2017).

    CAS  PubMed  Google Scholar 

  83. 83.

    Peacock, O. et al. Inflammation and MiR-21 pathways functionally interact to downregulate PDCD4 in colorectal cancer. PLOS ONE 9, e110267 (2014).

    PubMed  PubMed Central  Google Scholar 

  84. 84.

    Horiuchi, A., Iinuma, H., Akahane, T., Shimada, R. & Watanabe, T. Prognostic significance of PDCD4 expression and association with microRNA-21 in each Dukes’ stage of colorectal cancer patients. Oncol. Rep. 27, 1384–1392 (2012).

    CAS  PubMed  Google Scholar 

  85. 85.

    Sun, D. et al. MicroRNA-31 activates the RAS pathway and functions as an oncogenic MicroRNA in human colorectal cancer by repressing RAS p21 GTPase activating protein 1 (RASA1). J. Biol. Chem. 288, 9508–9518 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. 86.

    Manceau, G. et al. Hsa-miR-31-3p expression is linked to progression-free survival in patients with KRAS wild-type metastatic colorectal cancer treated with anti-EGFR therapy. Clin. Cancer Res. 20, 3338–3347 (2014).

    CAS  PubMed  Google Scholar 

  87. 87.

    Igarashi, H. et al. Association of microRNA-31-5p with clinical efficacy of anti-EGFR therapy in patients with metastatic colorectal cancer. Ann. Surg. Oncol. 22, 2640–2648 (2015).

    PubMed  Google Scholar 

  88. 88.

    Rmali, K. A., Puntis, M. C. A. & Jiang, W. G. Tumour-associated angiogenesis in human colorectal cancer. Colorectal Dis. 9, 3–14 (2007).

    CAS  PubMed  Google Scholar 

  89. 89.

    Zhang, Y. et al. Epigenetic silencing of miR-126 contributes to tumor invasion and angiogenesis in colorectal cancer. Oncol. Rep. 30, 1976–1984 (2013).

    CAS  PubMed  Google Scholar 

  90. 90.

    Yin, J. et al. Differential expression of serum miR-126, miR-141 and miR-21 as novel biomarkers for early detection of liver metastasis in colorectal cancer. Chin. J. Cancer Res. 26, 95–103 (2014).

    PubMed  PubMed Central  Google Scholar 

  91. 91.

    Liu, Y. et al. Low expression of microRNA-126 is associated with poor prognosis in colorectal cancer. Genes Chromosom. Cancer 53, 358–365 (2014).

    CAS  PubMed  Google Scholar 

  92. 92.

    Fiala, O. et al. The association of miR-126-3p, miR-126-5p and miR-664-3p expression profiles with outcomes of patients with metastatic colorectal cancer treated with bevacizumab. Tumour Biol. 39, 1010428317709283 (2017).

    PubMed  Google Scholar 

  93. 93.

    Quintero, E. et al. Colonoscopy versus fecal immunochemical testing in colorectal-cancer screening. N. Engl. J. Med. 366, 697–706 (2012).

    CAS  PubMed  Google Scholar 

  94. 94.

    Compton, C. C. Optimal pathologic staging: defining stage II disease. Clin. Cancer Res. 13, 6862s–6870s (2007).

    PubMed  Google Scholar 

  95. 95.

    He, N. et al. The pathological features of colorectal cancer determine the detection performance on blood ctDNA. Technol. Cancer Res. Treat. 17, 1533033818791794 (2018).

    PubMed  PubMed Central  Google Scholar 

  96. 96.

    Song, L., Jia, J., Peng, X., Xiao, W. & Li, Y. The performance of the SEPT9 gene methylation assay and a comparison with other CRC screening tests: a meta-analysis. Sci. Rep. 7, 1–12 (2017).

    Google Scholar 

  97. 97.

    Tänzer, M. et al. Performance of epigenetic markers SEPT9 and ALX4 in plasma for detection of colorectal precancerous lesions. PLOS ONE 5, e9061 (2010).

    PubMed  PubMed Central  Google Scholar 

  98. 98.

    Wu, D. et al. Detection of colorectal cancer using a simplified SEPT9 gene methylation assay is a reliable method for opportunistic screening. J. Mol. Diagn. 18, 535–545 (2016).

    CAS  PubMed  Google Scholar 

  99. 99.

    Bergheim, J. et al. Potential of quantitative SEPT9 and SHOX2 methylation in plasmatic circulating cell-free DNA as auxiliary staging parameter in colorectal cancer: a prospective observational cohort study. Br. J. Cancer 118, 1217–1228 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. 100.

    Church, T. R. et al. Prospective evaluation of methylated SEPT9 in plasma for detection of asymptomatic colorectal cancer. Gut 63, 317–325 (2014).

    CAS  PubMed  Google Scholar 

  101. 101.

    Fu, B. et al. Cell-free circulating methylated SEPT9 for noninvasive diagnosis and monitoring of colorectal cancer. Dis. Markers 2018, 6437104 (2018).

    PubMed  PubMed Central  Google Scholar 

  102. 102.

    Song, L. et al. The SEPT9 gene methylation assay is capable of detecting colorectal adenoma in opportunistic screening. Epigenomics 9, 599–610 (2017).

    CAS  PubMed  Google Scholar 

  103. 103.

    Li, M. et al. Sensitive digital quantification of DNA methylation in clinical samples. Nat. Biotechnol. 27, 858–863 (2009).

    PubMed  PubMed Central  Google Scholar 

  104. 104.

    Itzkowitz, S. H. et al. Improved fecal DNA test for colorectal cancer screening. Clin. Gastroenterol. Hepatol. 5, 111–117 (2007).

    CAS  PubMed  Google Scholar 

  105. 105.

    Baek, Y. H. et al. Stool methylation-specific polymerase chain reaction assay for the detection of colorectal neoplasia in Korean patients. Dis. Colon Rectum 52, 1452–1459; discussion 1459–1463 (2009).

    PubMed  Google Scholar 

  106. 106.

    Kisiel, J. B. et al. Stool DNA testing for the detection of colorectal neoplasia in patients with inflammatory bowel disease. Aliment. Pharmacol. Ther. 37, 546–554 (2013).

    CAS  PubMed  Google Scholar 

  107. 107.

    Lu, H. et al. DNA methylation analysis of SFRP2, GATA4/5, NDRG4 and VIM for the detection of colorectal cancer in fecal DNA. Oncol. Lett. 8, 1751–1756 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. 108.

    Chen, W. D. et al. Detection in fecal DNA of colon cancer-specific methylation of the nonexpressed vimentin gene. J. Natl Cancer Inst. 97, 1124–1132 (2005).

    CAS  PubMed  Google Scholar 

  109. 109.

    Carmona, F. J. et al. DNA methylation biomarkers for noninvasive diagnosis of colorectal cancer. Cancer Prev. Res. 6, 656–665 (2013).

    CAS  Google Scholar 

  110. 110.

    Ned, R. M., Melillo, S. & Marrone, M. Fecal DNA testing for colorectal cancer screening: the ColoSureTM test. PLOS Curr. 3, RRN1220 (2011).

    PubMed  PubMed Central  Google Scholar 

  111. 111.

    Tang, D. et al. Diagnostic and prognostic value of the methylation status of secreted frizzled-related protein 2 in colorectal cancer. Clin. Invest. Med. 34, 88–95 (2011).

    Google Scholar 

  112. 112.

    Barták, B. K. et al. Colorectal adenoma and cancer detection based on altered methylation pattern of SFRP1, SFRP2, SDC2, and PRIMA1 in plasma samples. Epigenetics 12, 751–763 (2017).

    PubMed  PubMed Central  Google Scholar 

  113. 113.

    Park, S.-K. et al. Is methylation analysis of SFRP2, TFPI2, NDRG4, and BMP3 promoters suitable for colorectal cancer screening in the Korean population? Intest. Res. 15, 495–501 (2017).

    PubMed  PubMed Central  Google Scholar 

  114. 114.

    Glöckner, S. C. et al. Methylation of TFPI2 in stool DNA: a potential novel biomarker for the detection of colorectal cancer. Cancer Res. 69, 4691–4699 (2009).

    PubMed  PubMed Central  Google Scholar 

  115. 115.

    Zhang, H., Zhu, Y.-Q. Q., Wu, Y.-Q. Q., Zhang, P. & Qi, J. Detection of promoter hypermethylation of Wnt antagonist genes in fecal samples for diagnosis of early colorectal cancer. World J. Gastroenterol. 20, 6329–6335 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. 116.

    Imperiale, T. F. et al. Multitarget stool DNA testing for colorectal-cancer screening. N. Engl. J. Med. 370, 1287–1297 (2014).

    CAS  PubMed  Google Scholar 

  117. 117.

    US Preventive Services Task Force et al. Screening for colorectal cancer: US preventive services task force recommendation statement. JAMA 315, 2564–2575 (2016).

    Google Scholar 

  118. 118.

    van Lanschot, M. C. J. et al. Molecular stool testing as an alternative for surveillance colonoscopy: a cross-sectional cohort study. BMC Cancer 17, 1–8 (2017).

    Google Scholar 

  119. 119.

    Vasen, H. F. A. et al. Revised guidelines for the clinical management of Lynch syndrome (HNPCC): recommendations by a group of European experts. Gut 62, 812–823 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. 120.

    Giardiello, F. M. et al. Guidelines on genetic evaluation and management of Lynch syndrome: a consensus statement by the US Multi-Society Task Force on Colorectal Cancer. Gastroenterology 147, 502–526 (2014).

    PubMed  PubMed Central  Google Scholar 

  121. 121.

    Anderson, J. C. Pathogenesis and management of serrated polyps: current status and future directions. Gut Liver 8, 582–589 (2014).

    PubMed  PubMed Central  Google Scholar 

  122. 122.

    Ogino, S. et al. A cohort study of tumoral LINE-1 hypomethylation and prognosis in colon cancer. J. Natl Cancer Inst. 100, 1734–1738 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. 123.

    Ahn, J. B. et al. DNA methylation predicts recurrence from resected stage III proximal colon cancer. Cancer 117, 1847–1854 (2011).

    CAS  PubMed  Google Scholar 

  124. 124.

    Rhee, Y.-Y. et al. Clinical outcomes of patients with microsatellite-unstable colorectal carcinomas depend on L1 methylation level. Ann. Surg. Oncol. 19, 3441–3448 (2012).

    PubMed  Google Scholar 

  125. 125.

    Nakayama, H. et al. Molecular detection of p16 promoter methylation in the serum of colorectal cancer patients. Cancer Lett. 188, 115–119 (2002).

    CAS  PubMed  Google Scholar 

  126. 126.

    Nakayama, H. et al. Molecular detection of p16 promoter methylation in the serum of recurrent colorectal cancer patients. Int. J. Cancer 105, 491–493 (2003).

    CAS  PubMed  Google Scholar 

  127. 127.

    Zou, H.-Z. et al. Detection of aberrant p16 methylation in the serum of colorectal cancer patients. Clin. Cancer Res. 8, 188–191 (2002).

    PubMed  Google Scholar 

  128. 128.

    Lecomte, T. et al. Detection of free-circulating tumor-associated DNA in plasma of colorectal cancer patients and its association with prognosis. Int. J. Cancer 100, 542–548 (2002).

    CAS  PubMed  Google Scholar 

  129. 129.

    Xing, X.-B. et al. The prognostic value of p16 hypermethylation in cancer: a meta-analysis. PLOS ONE 8, e66587 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. 130.

    Mitomi, H. et al. Aberrantp16((INK4a)) methylation is a frequent event in colorectal cancers: prognostic value and relation to mRNA expression and immunoreactivity. J. Cancer Res. Clin. Oncol. 136, 323–331 (2010).

    CAS  PubMed  Google Scholar 

  131. 131.

    Shen, L. et al. Association between DNA methylation and shortened survival in patients with advanced colorectal cancer treated with 5-fluorouracil based chemotherapy. Clin. Cancer Res. 13, 6093–6098 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. 132.

    Kim, J. C. et al. Promoter methylation of specific genes is associated with the phenotype and progression of colorectal adenocarcinomas. Ann. Surg. Oncol. 17, 1767–1776 (2010).

    PubMed  Google Scholar 

  133. 133.

    Liang, J. T. et al. Hypermethylation of the p16 gene in sporadic T3N0M0 stage colorectal cancers: association with DNA replication error and shorter survival. Oncology 57, 149–156 (1999).

    CAS  PubMed  Google Scholar 

  134. 134.

    Sun, W. et al. The role of plasma cell-free DNA detection in predicting preoperative chemoradiotherapy response in rectal cancer patients. Oncol. Rep. 31, 1466–1472 (2014).

    CAS  PubMed  Google Scholar 

  135. 135.

    Hochhauser, D. et al. 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. 12, 809–818 (2013).

    CAS  PubMed  Google Scholar 

  136. 136.

    Nagasaka, T. et al. Hypermethylation of O6-methylguanine-DNA methyltransferase promoter may predict nonrecurrence after chemotherapy in colorectal cancer cases. Clin. Cancer Res. 9, 5306–5312 (2003).

    CAS  PubMed  Google Scholar 

  137. 137.

    Amatu, A. 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. 19, 2265–2272 (2013).

    CAS  PubMed  Google Scholar 

  138. 138.

    Park, S. J. et al. TFAP2E methylation status and prognosis of patients with radically resected colorectal cancer. Oncology 88, 122–132 (2015).

    CAS  PubMed  Google Scholar 

  139. 139.

    Ebert, M. P. A. et al. TFAP2E-DKK4 and chemoresistance in colorectal cancer. N. Engl. J. Med. 366, 44–53 (2012).

    CAS  PubMed  Google Scholar 

  140. 140.

    Murcia, O. et al. TFAP2E methylation and expression status does not predict response to 5-FU-based chemotherapy in colorectal cancer. Clin. Cancer Res. 24, 2820–2827 (2018).

    CAS  PubMed  Google Scholar 

  141. 141.

    Herbst, A. et al. Methylated free-circulating HPP1 DNA is an early response marker in patients with metastatic colorectal cancer. Int. J. Cancer 140, 2134–2144 (2017).

    CAS  PubMed  Google Scholar 

  142. 142.

    Philipp, A. B. et al. Circulating cell-free methylated DNA and lactate dehydrogenase release in colorectal cancer. BMC Cancer 14, 245 (2014).

    PubMed  PubMed Central  Google Scholar 

  143. 143.

    Herbst, A. et al. Methylation of NEUROG1 in serum is a sensitive marker for the detection of early colorectal cancer. Am. J. Gastroenterol. 106, 1110–1118 (2011).

    CAS  PubMed  Google Scholar 

  144. 144.

    Wallner, M. et al. Methylation of serum DNA is an independent prognostic marker in colorectal cancer. Clin. Cancer Res. 12, 7347–7352 (2006).

    CAS  PubMed  Google Scholar 

  145. 145.

    Herbst, A. et al. Methylation of helicase-like transcription factor in serum of patients with colorectal cancer is an independent predictor of disease recurrence. Eur. J. Gastroenterol. Hepatol. 21, 565–569 (2009).

    CAS  PubMed  Google Scholar 

  146. 146.

    Huang, Z.-H., Li, L.-H., Yang, F. & Wang, J.-F. Detection of aberrant methylation in fecal DNA as a molecular screening tool for colorectal cancer and precancerous lesions. World J. Gastroenterol. 13, 950–954 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  147. 147.

    Ashktorab, H. et al. Global histone H4 acetylation and HDAC2 expression in colon adenoma and carcinoma. Dig. Dis. Sci. 54, 2109–2117 (2009).

    CAS  PubMed  Google Scholar 

  148. 148.

    Nakazawa, T. et al. Global histone modification of histone H3 in colorectal cancer and its precursor lesions. Hum. Pathol. 43, 834–842 (2012).

    CAS  PubMed  Google Scholar 

  149. 149.

    Karczmarski, J. et al. Histone H3 lysine 27 acetylation is altered in colon cancer. Clin. Proteom. 11, 24 (2014).

    Google Scholar 

  150. 150.

    Gezer, U. et al. Characterization of H3K9me3- and H4K20me3-associated circulating nucleosomal DNA by high-throughput sequencing in colorectal cancer. Tumour Biol. 34, 329–336 (2013).

    CAS  PubMed  Google Scholar 

  151. 151.

    Gezer, U. et al. Histone methylation marks on circulating nucleosomes as novel blood-based biomarker in colorectal cancer. Int. J. Mol. Sci. 16, 29654–29662 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  152. 152.

    Tamagawa, H. et al. The global histone modification pattern correlates with overall survival in metachronous liver metastasis of colorectal cancer. Oncol. Rep. 27, 637–642 (2012).

    CAS  PubMed  Google Scholar 

  153. 153.

    Yokoyama, Y. et al. Cancer-associated upregulation of histone H3 lysine 9 trimethylation promotes cell motility in vitro and drives tumor formation in vivo. Cancer Sci. 104, 889–895 (2013).

    CAS  PubMed  Google Scholar 

  154. 154.

    Benard, A. et al. Histone trimethylation at H3K4, H3K9 and H4K20 correlates with patient survival and tumor recurrence in early-stage colon cancer. BMC Cancer 14, 531 (2014).

    PubMed  PubMed Central  Google Scholar 

  155. 155.

    Benard, A. et al. Nuclear expression of histone deacetylases and their histone modifications predicts clinical outcome in colorectal cancer. Histopathology 66, 270–282 (2015).

    PubMed  Google Scholar 

  156. 156.

    Benard, A. et al. Prognostic value of polycomb proteins EZH2, BMI1 and SUZ12 and histone modification H3K27me3 in colorectal cancer. PLOS ONE 9, e108265 (2014).

    PubMed  PubMed Central  Google Scholar 

  157. 157.

    Bovell, L. et al. miRNAs are stable in colorectal cancer archival tissue blocks. Front. Biosci. 4, 1937–1940 (2012).

    Google Scholar 

  158. 158.

    Peng, Q. et al. The clinical role of microRNA-21 as a promising biomarker in the diagnosis and prognosis of colorectal cancer: a systematic review and meta-analysis. Oncotarget 8, 44893–44909 (2017).

    PubMed  PubMed Central  Google Scholar 

  159. 159.

    Zhang, Y., Guo, C.-C., Guan, D.-H., Yang, C.-H. & Jiang, Y.-H. Prognostic value of microRNA-224 in various cancers: a meta-analysis. Arch. Med. Res. 48, 472–482 (2017).

    CAS  PubMed  Google Scholar 

  160. 160.

    Hao, H. et al. Diagnostic and prognostic value of miR-106a in colorectal cancer. Oncotarget 8, 5038–5047 (2017).

    PubMed  Google Scholar 

  161. 161.

    Zhi, M. L., Liu, Z. J., Yi, X. Y., Zhang, L. J. & Bao, Y. X. Diagnostic performance of microRNA-29a for colorectal cancer: a meta-analysis. Genet. Mol. Res. 14, 18018–18025 (2015).

    CAS  PubMed  Google Scholar 

  162. 162.

    Yang, X. et al. MicroRNA-92a as a potential biomarker in diagnosis of colorectal cancer: a systematic review and meta-analysis. PLOS ONE 9, e88745 (2014).

    PubMed  PubMed Central  Google Scholar 

  163. 163.

    Sun, G. et al. Signature miRNAs in colorectal cancers were revealed using a bias reduction small RNA deep sequencing protocol. Oncotarget 7, 3857–3872 (2016).

    PubMed  Google Scholar 

  164. 164.

    Bastaminejad, S. et al. Investigation of microRNA-21 expression levels in serum and stool as a potential non-invasive biomarker for diagnosis of colorectal cancer. Iran. Biomed. J. 21, 106–113 (2017).

    PubMed  PubMed Central  Google Scholar 

  165. 165.

    Toiyama, Y. et al. Serum miR-21 as a diagnostic and prognostic biomarker in colorectal cancer. J. Natl Cancer Inst. 105, 849–859 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  166. 166.

    Mima, K. et al. MicroRNA MIR21 (miR-21) and PTGS2 expression in colorectal cancer and patient survival. Clin. Cancer Res. 22, 3841–3848 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  167. 167.

    Caramés, C. et al. MicroRNA-21 predicts response to preoperative chemoradiotherapy in locally advanced rectal cancer. Int. J. Colorectal Dis. 30, 899–906 (2015).

    PubMed  Google Scholar 

  168. 168.

    Schetter, A. J. et al. MicroRNA expression profiles associated with prognosis and therapeutic outcome in colon adenocarcinoma. JAMA 299, 425–436 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  169. 169.

    Liu, K. et al. Increased expression of microRNA-21 and its association with chemotherapeutic response in human colorectal cancer. J. Int. Med. Res. 39, 2288–2295 (2011).

    CAS  PubMed  Google Scholar 

  170. 170.

    Ng, E. K. O. et al. Differential expression of microRNAs in plasma of patients with colorectal cancer: a potential marker for colorectal cancer screening. Gut 58, 1375–1381 (2009).

    CAS  PubMed  Google Scholar 

  171. 171.

    Wu, C. W. et al. Detection of miR-92a and miR-21 in stool samples as potential screening biomarkers for colorectal cancer and polyps. Gut 61, 739–745 (2012).

    CAS  PubMed  Google Scholar 

  172. 172.

    Uratani, R. et al. Diagnostic potential of cell-free and exosomal MicroRNAs in the identification of patients with high-risk colorectal adenomas. PLOS ONE 11, e0160722 (2016).

    PubMed  PubMed Central  Google Scholar 

  173. 173.

    Ke, T.-W., Wei, P.-L., Yeh, K.-T., Chen, W. T.-L. & Cheng, Y.-W. MiR-92a promotes cell metastasis of colorectal cancer through PTEN-mediated PI3K/AKT pathway. Ann. Surg. Oncol. 22, 2649–2655 (2015).

    PubMed  Google Scholar 

  174. 174.

    Elshafei, A., Shaker, O., Abd El-Motaal, O. & Salman, T. The expression profiling of serum miR-92a, miR-375, and miR-760 in colorectal cancer: an Egyptian study. Tumour Biol. 39, 1010428317705765 (2017).

    PubMed  Google Scholar 

  175. 175.

    Zhou, J. et al. 5-Fluorouracil and oxaliplatin modify the expression profiles of microRNAs in human colon cancer cells in vitro. Oncol. Rep. 23, 121–128 (2010).

    CAS  PubMed  Google Scholar 

  176. 176.

    Du, M. et al. Clinical potential role of circulating microRNAs in early diagnosis of colorectal cancer patients. Carcinogenesis 35, 2723–2730 (2014).

    CAS  PubMed  Google Scholar 

  177. 177.

    Kanaan, Z. et al. Plasma miR-21: a potential diagnostic marker of colorectal cancer. Ann. Surg. 256, 544–551 (2012).

    PubMed  Google Scholar 

  178. 178.

    Ogata-Kawata, H. et al. Circulating exosomal microRNAs as biomarkers of colon cancer. PLOS ONE 9, e92921 (2014).

    PubMed  PubMed Central  Google Scholar 

  179. 179.

    Liu, G.-H. H. et al. Serum miR-21 and miR-92a as biomarkers in the diagnosis and prognosis of colorectal cancer. Tumour Biol. 34, 2175–2181 (2013).

    CAS  PubMed  Google Scholar 

  180. 180.

    Liu, H.-N. et al. Serum microRNA signatures and metabolomics have high diagnostic value in colorectal cancer using two novel methods. Cancer Sci. 109, 1185–1194 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  181. 181.

    Chang, P.-Y. et al. MicroRNA-223 and microRNA-92a in stool and plasma samples act as complementary biomarkers to increase colorectal cancer detection. Oncotarget 7, 10663–10675 (2016).

    PubMed  PubMed Central  Google Scholar 

  182. 182.

    Herreros-Villanueva, M. et al. Plasma microRNA signature validation for early detection of colorectal cancer. Clin. Transl. Gastroenterol. 10, e00003 (2019).

    PubMed  PubMed Central  Google Scholar 

  183. 183.

    Zheng, G. et al. Serum microRNA panel as biomarkers for early diagnosis of colorectal adenocarcinoma. Br. J. Cancer 111, 1985–1992 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  184. 184.

    Huang, Z. et al. Plasma microRNAs are promising novel biomarkers for early detection of colorectal cancer. Int. J. Cancer 127, 118–126 (2010).

    CAS  PubMed  Google Scholar 

  185. 185.

    Kjersem, J. B. et al. Plasma microRNAs predicting clinical outcome in metastatic colorectal cancer patients receiving first-line oxaliplatin-based treatment. Mol. Oncol. 8, 59–67 (2014).

    CAS  PubMed  Google Scholar 

  186. 186.

    Zhao, W., Song, M., Zhang, J., Kuerban, M. & Wang, H. Combined identification of long non-coding RNA CCAT1 and HOTAIR in serum as an effective screening for colorectal carcinoma. Int. J. Clin. Exp. Pathol. 8, 14131–14140 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  187. 187.

    Svoboda, M. et al. HOTAIR long non-coding RNA is a negative prognostic factor not only in primary tumors, but also in the blood of colorectal cancer patients. Carcinogenesis 35, 1510–1515 (2014).

    CAS  PubMed  Google Scholar 

  188. 188.

    Alaiyan, B. et al. Differential expression of colon cancer associated transcript1 (CCAT1) along the colonic adenoma-carcinoma sequence. BMC Cancer 13, 196 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  189. 189.

    Nissan, A. et al. Colon cancer associated transcript-1: a novel RNA expressed in malignant and pre-malignant human tissues. Int. J. Cancer 130, 1598–1606 (2012).

    CAS  PubMed  Google Scholar 

  190. 190.

    He, X. et al. C-Myc-activated long noncoding RNA CCAT1 promotes colon cancer cell proliferation and invasion. Tumour Biol. 35, 12181–12188 (2014).

    CAS  PubMed  Google Scholar 

  191. 191.

    Ozawa, T. et al. CCAT1 and CCAT2 long noncoding RNAs, located within the 8q.24.21 ‘gene desert’, serve as important prognostic biomarkers in colorectal cancer. Ann. Oncol. 28, 1882–1888 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  192. 192.

    Yin, D. et al. Long noncoding RNA GAS5 affects cell proliferation and predicts a poor prognosis in patients with colorectal cancer. Med. Oncol. 31, 253 (2014).

    PubMed  Google Scholar 

  193. 193.

    Li, Y. et al. Long non-coding RNA growth arrest specific transcript 5 acts as a tumour suppressor in colorectal cancer by inhibiting interleukin-10 and vascular endothelial growth factor expression. Oncotarget 8, 13690–13702 (2017).

    PubMed  PubMed Central  Google Scholar 

  194. 194.

    Baretti, M. & Azad, N. S. The role of epigenetic therapies in colorectal cancer. Curr. Probl. Cancer 42, 530–547 (2018).

    PubMed  Google Scholar 

  195. 195.

    Verheul, H. M. W., Qian, D. Z., Carducci, M. A. & Pili, R. Sequence-dependent antitumor effects of differentiation agents in combination with cell cycle-dependent cytotoxic drugs. Cancer Chemother. Pharmacol. 60, 329–339 (2007).

    CAS  PubMed  Google Scholar 

  196. 196.

    Abdelfatah, E., Kerner, Z., Nanda, N. & Ahuja, N. Epigenetic therapy in gastrointestinal cancer: the right combination. Therap. Adv. Gastroenterol. 9, 560–579 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  197. 197.

    Ikehata, M. et al. Different effects of epigenetic modifiers on the cytotoxicity induced by 5-fluorouracil, irinotecan or oxaliplatin in colon cancer cells. Biol. Pharm. Bull. 37, 67–73 (2014).

    CAS  PubMed  Google Scholar 

  198. 198.

    Flis, S., Gnyszka, A. & Flis, K. DNA methyltransferase inhibitors improve the effect of chemotherapeutic agents in SW48 and HT-29 colorectal cancer cells. PLOS ONE 9, e92305 (2014).

    PubMed  PubMed Central  Google Scholar 

  199. 199.

    Overman, M. J. et al. Phase I/II study of azacitidine and capecitabine/oxaliplatin (CAPOX) in refractory CIMP-high metastatic colorectal cancer: evaluation of circulating methylated vimentin. Oncotarget 7, 67495–67506 (2016).

    PubMed  PubMed Central  Google Scholar 

  200. 200.

    Kim, J. C. et al. In vitro evaluation of histone deacetylase inhibitors as combination agents for colorectal cancer. Anticancer Res. 29, 3027–3034 (2009).

    CAS  PubMed  Google Scholar 

  201. 201.

    Fakih, M. G., Groman, A., McMahon, J., Wilding, G. & Muindi, J. R. A randomized phase II study of two doses of vorinostat in combination with 5-FU/LV in patients with refractory colorectal cancer. Cancer Chemother. Pharmacol. 69, 743–751 (2012).

    CAS  PubMed  Google Scholar 

  202. 202.

    Humeniuk, R., Mishra, P. J., Bertino, J. R. & Banerjee, D. Epigenetic reversal of acquired resistance to 5-fluorouracil treatment. Mol. Cancer Ther. 8, 1045–1054 (2009).

    CAS  PubMed  Google Scholar 

  203. 203.

    Fazzone, W., Wilson, P. M., Labonte, M. J., Lenz, H.-J. & Ladner, R. D. Histone deacetylase inhibitors suppress thymidylate synthase gene expression and synergize with the fluoropyrimidines in colon cancer cells. Int. J. Cancer 125, 463–473 (2009).

    CAS  PubMed  Google Scholar 

  204. 204.

    Lou, Y. et al. Combination of gefitinib and DNA methylation inhibitor decitabine exerts synergistic anti-cancer activity in colon cancer cells. PLOS ONE 9, e97719 (2014).

    PubMed  PubMed Central  Google Scholar 

  205. 205.

    Mao, M. et al. Resistance to BRAF inhibition in BRAF-mutant colon cancer can be overcome with PI3K inhibition or demethylating agents. Clin. Cancer Res. 19, 657–667 (2013).

    CAS  PubMed  Google Scholar 

  206. 206.

    Abaza, M.-S. I., Bahman, A.-M. & Al-Attiyah, R. Superior antimitogenic and chemosensitization activities of the combination treatment of the histone deacetylase inhibitor apicidin and proteasome inhibitors on human colorectal cancer cells. Int. J. Oncol. 44, 105–128 (2014).

    CAS  PubMed  Google Scholar 

  207. 207.

    Garrido-Laguna, I. et al. A phase I/II study of decitabine in combination with panitumumab in patients with wild-type (wt) KRAS metastatic colorectal cancer. Invest. New Drugs 31, 1257–1264 (2013).

    CAS  PubMed  Google Scholar 

  208. 208.

    He, G., Wang, Y., Pang, X. & Zhang, B. Inhibition of autophagy induced by TSA sensitizes colon cancer cell to radiation. Tumour Biol. 35, 1003–1011 (2014).

    CAS  PubMed  Google Scholar 

  209. 209.

    Kim, K. et al. Eradication of metastatic mouse cancers resistant to immune checkpoint blockade by suppression of myeloid-derived cells. Proc. Natl Acad. Sci. USA 111, 11774–11779 (2014).

    CAS  PubMed  Google Scholar 

  210. 210.

    Yu, G. et al. Low-dose decitabine enhances the effect of PD-1 blockade in colorectal cancer with microsatellite stability by re-modulating the tumor microenvironment. Cell. Mol. Immunol. 16, 1–9 (2018).

    Google Scholar 

  211. 211.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/study/NCT02260440 (2019).

  212. 212.

    Lee, J. J. et al. Phase 2 study of pembrolizumab in combination with azacitidine in subjects with metastatic colorectal cancer. J. Clin. Oncol. 35, 3054–3054 (2017).

    Google Scholar 

  213. 213.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02512172 (2019).

  214. 214.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02437136 (2018).

  215. 215.

    Romain, B. et al. Histone hypoacetylation contributes to CXCL12 downregulation in colon cancer: impact on tumor growth and cell migration. Oncotarget 8, 38351–38366 (2017).

    PubMed  PubMed Central  Google Scholar 

  216. 216.

    Huang, Z. et al. Lysine-specific demethylase 1 (LSD1/KDM1A) contributes to colorectal tumorigenesis via activation of the Wnt/β-catenin pathway by down-regulating Dickkopf-1 (DKK1) [corrected]. PLOS ONE 8, e70077 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  217. 217.

    Hsu, H.-C. et al. CBB1003, a lysine-specific demethylase 1 inhibitor, suppresses colorectal cancer cells growth through down-regulation of leucine-rich repeat-containing G-protein-coupled receptor 5 expression. J. Cancer Res. Clin. Oncol. 141, 11–21 (2015).

    CAS  PubMed  Google Scholar 

  218. 218.

    Rotili, D. et al. Pan-histone demethylase inhibitors simultaneously targeting Jumonji C and lysine-specific demethylases display high anticancer activities. J. Med. Chem. 57, 42–55 (2014).

    CAS  PubMed  Google Scholar 

  219. 219.

    Beg, M. S. et al. Phase I study of MRX34, a liposomal miR-34a mimic, administered twice weekly in patients with advanced solid tumors. Invest. New Drugs 35, 180–188 (2017).

    CAS  PubMed  Google Scholar 

  220. 220.

    Titze-de-Almeida, R., David, C. & Titze-de-Almeida, S. S. The race of 10 synthetic RNAi-based drugs to the pharmaceutical market. Pharm. Res. 34, 1339–1363 (2017).

    CAS  PubMed  Google Scholar 

  221. 221.

    Watts, J. K. & Corey, D. R. Silencing disease genes in the laboratory and the clinic. J. Pathol. 226, 365–379 (2012).

    CAS  PubMed  Google Scholar 

  222. 222.

    Singh, A., Trivedi, P. & Jain, N. K. Advances in siRNA delivery in cancer therapy. Artif. Cells Nanomed. Biotechnol. 46, 274–283 (2018).

    CAS  PubMed  Google Scholar 

  223. 223.

    Nedaeinia, R. et al. Current status and perspectives regarding LNA-anti-miR oligonucleotides and microRNA miR-21 inhibitors as a potential therapeutic option in treatment of colorectal cancer. J. Cell Biochem. 118, 4129–4140 (2017).

    CAS  PubMed  Google Scholar 

  224. 224.

    Turajlic, S., Sottoriva, A., Graham, T. & Swanton, C. Resolving genetic heterogeneity in cancer. Nat. Rev. Genet. 20, 404–416 (2019).

    CAS  PubMed  Google Scholar 

  225. 225.

    Martínez-Cardús, A. et al. Epigenetic homogeneity within colorectal tumors predicts shorter relapse-free and overall survival times for patients with locoregional cancer. Gastroenterology 151, 961–972 (2016).

    PubMed  Google Scholar 

  226. 226.

    Davalos, V. et al. Dynamic epigenetic regulation of the microRNA-200 family mediates epithelial and mesenchymal transitions in human tumorigenesis. Oncogene 31, 2062–2074 (2012).

    CAS  PubMed  Google Scholar 

  227. 227.

    Chen, T. et al. MicroRNA-31 contributes to colorectal cancer development by targeting factor inhibiting HIF-1alpha (FIH-1). Cancer Biol. Ther. 15, 516–523 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  228. 228.

    Tang, W. et al. MicroRNA-29a promotes colorectal cancer metastasis by regulating matrix metalloproteinase 2 and E-cadherin via KLF4. Br. J. Cancer 110, 450–458 (2014).

    CAS  PubMed  Google Scholar 

  229. 229.

    Nagel, R. et al. Regulation of the adenomatous polyposis coli gene by the miR-135 family in colorectal cancer. Cancer Res. 68, 5795–5802 (2008).

    CAS  PubMed  Google Scholar 

  230. 230.

    Toiyama, Y. et al. A panel of methylated microRNA biomarkers for identifying high-risk patients with ulcerative colitis-associated colorectal cancer. Gastroenterology 153, 1634–1646.e8 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

A.G. gratefully acknowledges grant support from the National Cancer Institute (NCI) of the NIH (CA72851, CA184792, CA202797, CA187956 and CA214254), the Cancer Prevention Research Institute of Texas (RP140784) and the Baylor Foundation and Baylor Scott & White Research Institute. This work was also supported by the Instituto de Salud Carlos III (grant PI16/00766 to F.B.) through the Plan Estatal de Investigación Científica y Técnica y de Innovación, and was co-funded by the European Regional Development Fund (ERDF). The Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD) is funded by the Instituto de Salud Carlos III. Part of this work was also co-funded by the Hospital Clínic’s Premi Fi de Residència (G.J.).

Review criteria

Unbiased PubMed searches were performed for each potential epigenetic biomarker in combination with relevant search terms for colorectal cancer, after which titles and abstracts of studies from the past ten years were screened for relevance. Meta-analyses, reviews and studies evaluating biomarker panels were also included. The most promising diagnostic, prognostic and predictive biomarker candidates were selected and ranked based on the total number of identified publications, the statistical design and power of the study, independent validation, potential as non-invasive biomarkers, and biological functionality of the biomarkers. Detailed Review criteria can be found in Supplementary Box 1.

Author information

Affiliations

Authors

Contributions

A.G., L.M. and F.B. made substantial contributions to discussion of the article contents. All authors researched data for the article, wrote the manuscript, and reviewed and/or edited the manuscript before submission.

Corresponding authors

Correspondence to Francesc Balaguer or Ajay Goel.

Ethics declarations

Competing interests

F.B. declares that he has endoscopic equipment on loan from Fujifilm, and has received an honorarium for consultancy from Sysmex and speaker’s fees from Norgine. The other authors declare no competing interests.

Additional information

Peer review information

Nature Reviews Gastroenterology & Hepatology thanks M. Esteller, R. Nishihara and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note

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

Related links

deepBase: http://rna.sysu.edu.cn/deepBase/

NONCODE: http://www.noncode.org

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Jung, G., Hernández-Illán, E., Moreira, L. et al. Epigenetics of colorectal cancer: biomarker and therapeutic potential. Nat Rev Gastroenterol Hepatol 17, 111–130 (2020). https://doi.org/10.1038/s41575-019-0230-y

Download citation

Further reading