Skip to main content
SpringerLink
Log in

The Role of DNA Methylation in Renal Cell Carcinoma

  • Review Article
  • Published:
Molecular Diagnosis & Therapy Aims and scope Submit manuscript

Abstract

Renal cell carcinoma (RCC) is the most common kidney cancer and includes several molecular and histological subtypes with different clinical characteristics. While survival rates are high if RCC is diagnosed when still confined to the kidney and treated definitively, there are no specific diagnostic screening tests available and symptoms are rare in early stages of the disease. Management of advanced RCC has changed significantly with the advent of targeted therapies, yet survival is usually increased by months due to acquired resistance to these therapies. DNA methylation, the covalent addition of a methyl group to a cytosine, is essential for normal development and transcriptional regulation, but becomes altered commonly in cancer. These alterations result in broad transcriptional changes, including in tumor suppressor genes. Because DNA methylation is one of the earliest molecular changes in cancer and is both widespread and stable, its role in cancer biology, including RCC, has been extensively studied. In this review, we examine the role of DNA methylation in RCC disease etiology and progression, the preclinical use of DNA methylation alterations as diagnostic, prognostic and predictive biomarkers, and the potential for DNA methylation-directed therapies.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Jonasch E, Gao J, Rathmell WK. Renal cell carcinoma. BMJ. 2014;349:g4797.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Chen F, Zhang Y, Şenbabaoğlu Y, Ciriello G, Yang L, Reznik E, et al. Multilevel genomics-based taxonomy of renal cell carcinoma. Cell Rep. 2016;14:2476–89.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Hsieh JJ, Le V, Cao D, Cheng EH, Creighton CJ. Genomic classifications of renal cell carcinoma: a critical step towards the future application of personalized kidney cancer care with panomics precision. J Pathol. 2018;244:525–37.

    Article  PubMed  Google Scholar 

  4. Lightfoot N, Conlon M, Kreiger N, Bissett R, Desai M, Warde P, et al. Impact of noninvasive imaging on increased incidental detection of renal cell carcinoma. Eur Urol. 2000;37:521–7.

    Article  PubMed  CAS  Google Scholar 

  5. Silverman SG, Israel GM, Herts BR, Richie JP. Management of the incidental renal mass. Radiology. 2008;249:16–31.

    Article  PubMed  Google Scholar 

  6. Howlader N, Noone A, Krapcho M, Garshell J, Miller D, Altekruse S, et al. SEER cancer statistics review, 1975–2012. Rockville: National Cancer Institute; 2015.

    Google Scholar 

  7. Hsieh JJ, Purdue MP, Signoretti S, Swanton C, Albiges L, Schmidinger M, et al. Renal cell carcinoma. Nat Rev Dis Prim. 2017;3:17009.

    Article  PubMed  Google Scholar 

  8. Jonasch E, Futreal PA, Davis IJ, Bailey ST, Kim WY, Brugarolas J, et al. State of the science: an update on renal cell carcinoma. Mol Cancer Res. 2012;10:859–80.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Linehan WM, Ricketts CJ. Decade in review-kidney cancer: discoveries, therapies and opportunities. Nat Rev Urol. 2014;11:614–6.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA Cancer J Clin. 2017;67:7–30. https://doi.org/10.3322/caac.21387.

    Article  PubMed  Google Scholar 

  11. Gnarra JR, Tory K, Weng Y, Schmidt L, Wei MH, Li H, et al. Mutations of the VHL tumour suppressor gene in renal carcinoma. Nat Genet. 1994;7:85–90.

    Article  PubMed  CAS  Google Scholar 

  12. Creighton CJ, Morgan M, Gunaratne PH, Wheeler DA, Gibbs RA, Gordon Robertson A, et al. Comprehensive molecular characterization of clear cell renal cell carcinoma. Nature. 2013;499:43–9.

    Article  CAS  Google Scholar 

  13. Rankin EB, Tomaszewski JE, Haase VH. Renal cyst development in mice with conditional inactivation of the von Hippel–Lindau tumor suppressor. Cancer Res. 2006;66:2576–83.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Kapitsinou PP, Haase VH. The VHL tumor suppressor and HIF: insights from genetic studies in mice. Cell Death Differ. 2008;15:650–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Cancer Genome Atlas Research Network. Comprehensive molecular characterization of clear cell renal cell carcinoma. Nature. 2013;499:43–9.

    Article  Google Scholar 

  16. Varela I, Tarpey P, Raine K, Huang D, Ong CK, Stephens P, et al. Exome sequencing identifies frequent mutation of the SWI/SNF complex gene PBRM1 in renal carcinoma. Nature. 2011;469:539–42.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Ricketts CJ, De Cubas AA, Fan H, Smith CC, Lang M, Reznik E, et al. The cancer genome atlas comprehensive molecular characterization of renal cell carcinoma. Cell Rep. 2018;23:313–26.

    Article  PubMed  CAS  Google Scholar 

  18. Nargund AM, Pham CG, Dong Y, Wang PI, Osmangeyoglu HU, Xie Y, et al. The SWI/SNF protein PBRM1 restrains VHL-loss-driven clear cell renal cell carcinoma. Cell Rep. 2017;18:2893–906.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Montero LM, Filipski J, Gil P, Capel J, Martinez-Zapater JM, Salinas J. The distribution of 5-methylcytosine in the nuclear genome of plants. Nucleic Acids Res. 1992;20:3207–10.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Laird PW, Jaenisch R. DNA methylation and cancer. Hum Mol Genet. 1994;3:1487–95.

    Article  PubMed  CAS  Google Scholar 

  21. Ushijima T. Detection and interpretation of altered methylation patterns in cancer cells. Nat Rev Cancer. 2005;5:223–31.

    Article  PubMed  CAS  Google Scholar 

  22. Sharma S, Kelly TK, Jones PA. Epigenetics in cancer. Carcinogenesis. 2010;31:27–36.

    Article  PubMed  CAS  Google Scholar 

  23. Tsai H-C, Baylin SB. Cancer epigenetics: linking basic biology to clinical medicine. Cell Res. 2011;21:502–17.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Wu P, Cao Z, Wu S. New progress of epigenetic biomarkers in urological cancer. Dis Markers. 2016;2016:1–8.

    Google Scholar 

  25. Baylin SB, Jones PA. A decade of exploring the cancer epigenome—biological and translational implications. Nat Rev Cancer. 2011;11:726–34.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Kanai Y. Genome-wide DNA methylation profiles in precancerous conditions and cancers. Cancer Sci. 2010;101:36–45.

    Article  PubMed  CAS  Google Scholar 

  27. Arai E, Kanai Y. Genetic and epigenetic alterations during renal carcino-genesis. Int J Clin Pathol. 2011;4:58–73.

    Google Scholar 

  28. NCBI Resource Coordinators. Database resources of the national center for biotechnology information. Nucleic Acids Res. 2017;45:D12–7.

    Article  Google Scholar 

  29. Herman JG, Latif F, Weng Y, Lerman MI, Zbar B, Liu S, et al. Silencing of the VHL tumor-suppressor gene by DNA methylation in renal carcinoma. Proc Natl Acad Sci USA. 1994;91:9700–4.

    Article  PubMed  CAS  Google Scholar 

  30. Clifford SC, Prowse AH, Affara NA, Buys CH, Maher ER. Inactivation of the von Hippel-Lindau (VHL) tumour suppressor gene and allelic losses at chromosome arm 3p in primary renal cell carcinoma: evidence for a VHL-independent pathway in clear cell renal tumourigenesis. Genes Chromosomes Cancer. 1998;22:200–9.

    Article  PubMed  CAS  Google Scholar 

  31. Yang L, Zhao Z, Zhao S, Chen C, Cong X, Li Z, et al. The clinicopathological significance of epigenetic silencing of VHL promoter and renal cell carcinoma: a meta-analysis. Cell Physiol Biochem. 2016;40:1465–72.

    Article  PubMed  CAS  Google Scholar 

  32. Donninger H, Vos MD, Clark GJ. The RASSF1A tumor suppressor. J Cell Sci. 2007;120:3163–72.

    Article  PubMed  CAS  Google Scholar 

  33. Morrissey C, Martinez A, Zatyka M, Agathanggelou A, Honorio S, Astuti D, et al. Epigenetic inactivation of the RASSF1A 3p21.3 tumor suppressor gene in both clear cell and papillary renal cell carcinoma. Cancer Res. 2001;61:7277–81.

    PubMed  CAS  Google Scholar 

  34. Huang YQ, Guan H, Liu CH, Liu DC, Xu B, Jiang L, et al. Association between RASSF1A promoter methylation and renal cell cancer susceptibility: a meta-analysis. Genet Mol Res. 2016. https://doi.org/10.4238/gmr.15026994.

    Article  PubMed  Google Scholar 

  35. Yu G-S, Lai C-Y, Xu Y, Bu C-F, Su Z-X. Aberrant methylation of RASSF1A gene contribute to the risk of renal cell carcinoma: a meta-analysis. Asian Pac J Cancer Prev. 2015;16:4665–9.

    Article  PubMed  Google Scholar 

  36. Wang J, Ren Y, Guo X, Cheng H, Ye Y, Qi J, et al. Alterations in enhancer of zeste homolog 2, matrix metalloproteinase-2 and tissue inhibitor of metalloproteinase-2 expression are associated with ex vivo and in vitro bone metastasis in renal cell carcinoma. Mol Med Rep. 2015;11:3585–92.

    Article  PubMed  CAS  Google Scholar 

  37. Shenoy N, Vallumsetla N, Zou Y, Galeas JN, Shrivastava M, Hu C, et al. Role of DNA methylation in renal cell carcinoma. J Hematol Oncol. 2015;8:88.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Morris MR, Ricketts CJ, Gentle D, McRonald F, Carli N, Khalili H, et al. Genome-wide methylation analysis identifies epigenetically inactivated candidate tumour suppressor genes in renal cell carcinoma. Oncog Nat Publ Group. 2011;30:1390–401.

    CAS  Google Scholar 

  39. McRonald FE, Morris MR, Gentle D, Winchester L, Baban D, Ragoussis J, et al. CpG methylation profiling in VHL related and VHL unrelated renal cell carcinoma. Mol Cancer. 2009;8:31.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Arai E, Ushijima S, Tsuda H. Genetic clustering of clear cell renal cell carcinoma based on array-comparative genomic hybridization: its association with DNA methylation alteration and patient outcome. Clin Cancer Res. 2008;14:5531–9.

    Article  PubMed  CAS  Google Scholar 

  41. Arai E, Chiku S, Mori T, Gotoh M, Nakagawa T, Fujimoto H, et al. Single-CpG-resolution methylome analysis identifies clinicopathologically aggressive CpG island methylator phenotype clear cell renal cell carcinomas. Carcinogenesis. 2012;33:1487–93.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Mendoza-Perez J, Gu J, Herrera LA, Tannir NM, Matin SF, Karam JA, et al. Genomic DNA hypomethylation and risk of renal cell carcinoma: a case–control study. Clin Cancer Res. 2016;22:2074–82.

    Article  PubMed  CAS  Google Scholar 

  43. Ramakrishnan N, Bose R. Analysis of distribution of DNA methylation in kidney-renal-clear-cell-carcinoma specific genes using entropy. Genom Data. 2016;10:109–13.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Hu CY, Mohtat D, Yu Y, Ko Y-A, Shenoy N, Bhattacharya S, et al. Kidney cancer is characterized by aberrant methylation of tissue-specific enhancers that are prognostic for overall survival. Clin Cancer Res. 2014;20:4349–60.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. Liu Y, Sun L, Fong P, Yang J, Zhang Z, Yin S, et al. An association between overexpression of DNA methyltransferase 3B4 and clear cell renal cell carcinoma. Oncotarget Impact J. 2017;8:19712–22.

    Google Scholar 

  46. Mahalingaiah PKS, Ponnusamy L, Singh KP. Oxidative stress-induced epigenetic changes associated with malignant transformation of human kidney epithelial cells. Oncotarget. 2016;8:11127–43.

    PubMed Central  Google Scholar 

  47. Wagner EJ, Carpenter PB. Understanding the language of Lys36 methylation at histone H3. Nat Rev Mol Cell Biol. 2012;13:115–26.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. Tiedemann RL, Hlady RA, Hanavan PD, Lake DF, Tibes R, Lee J-H, et al. Dynamic reprogramming of DNA methylation in SETD2-deregulated renal cell carcinoma. Oncotarget. 2016;7:1927–46.

    Article  PubMed  Google Scholar 

  49. Liu L, Guo R, Zhang X, Liang Y, Kong F, Wang J, et al. Loss of SETD2, but not H3K36me3, correlates with aggressive clinicopathological features of clear cell renal cell carcinoma patients. Biosci Trends. 2017;11:214–20.

    Article  PubMed  CAS  Google Scholar 

  50. Wang Y, Guo X, Bray MJ, Ding Z, Zhao Z. An integrative genomics approach for identifying novel functional consequences of PBRM1 truncated mutations in clear cell renal cell carcinoma (ccRCC). BMC Genom. 2016;17:515.

    Article  CAS  Google Scholar 

  51. He C, Zhao X, Jiang H, Zhong Z, Xu R. Demethylation of miR-10b plays a suppressive role in ccRCC cells. Int J Clin Exp Pathol. 2015;8:10595–604.

    PubMed  PubMed Central  CAS  Google Scholar 

  52. Hildebrandt MAT, Gu J, Lin J, Ye Y, Tan W, Tamboli P, et al. Hsa-miR-9 methylation status is associated with cancer development and metastatic recurrence in patients with clear cell renal cell carcinoma. Oncogene. 2010;29:5724–8.

    Article  PubMed  CAS  Google Scholar 

  53. Johnson DC, Vukina J, Smith AB, Meyer A-M, Wheeler SB, Kuo T-M, et al. Preoperatively misclassified, surgically removed benign renal masses: a systematic review of surgical series and United States population level burden estimate. J Urol. 2015;193:30–5.

    Article  PubMed  Google Scholar 

  54. Haas NB, Nathanson KL. Hereditary kidney cancer syndromes. Adv Chronic Kidney Dis. 2014;21:81–90.

    Article  PubMed  Google Scholar 

  55. Mikeska T, Bock C, Do H, Dobrovic A. DNA methylation biomarkers in cancer: progress towards clinical implementation. Expert Rev Mol Diagn. 2012;12:473–87.

    Article  PubMed  CAS  Google Scholar 

  56. Battagli C, Uzzo RG, Dulaimi E, Ibanez de Caceres I, Krassenstein R, Al-Saleem T, et al. Promoter hypermethylation of tumor suppressor genes in urine from kidney cancer patients. Cancer Res. 2003;63:8695–9.

    PubMed  CAS  Google Scholar 

  57. Hoque MO, Begum S, Topaloglu O, Jeronimo C, Mambo E, Westra WH, et al. Quantitative detection of promoter hypermethylation of multiple genes in the tumor, urine, and serum DNA of patients with renal cancer. Cancer Res. 2004;64:5511–7.

    Article  PubMed  CAS  Google Scholar 

  58. Hauser S, Zahalka T, Fechner G, Müller SC, Ellinger J. Serum DNA hypermethylation in patients with kidney cancer: results of a prospective study. Anticancer Res. 2013;33:4651–6.

    PubMed  CAS  Google Scholar 

  59. de Martino M, Klatte T, Haitel A, Marberger M. Serum cell-free DNA in renal cell carcinoma: a diagnostic and prognostic marker. Cancer. 2012;118:82–90. https://doi.org/10.1002/cncr.26254.

    Article  PubMed  CAS  Google Scholar 

  60. Skrypkina I, Tsyba L, Onyshchenko K, Morderer D, Kashparova O, Nikolaienko O, et al. Concentration and methylation of cell-free DNA from blood plasma as diagnostic markers of renal cancer. Dis Markers. 2016;2016:1–10.

    Article  Google Scholar 

  61. Lasseigne BN, Burwell TC, Patil MA, Absher DM, Brooks JD, Myers RM. DNA methylation profiling reveals novel diagnostic biomarkers in renal cell carcinoma. BMC Med. 2014;12:235.

    Article  PubMed  PubMed Central  Google Scholar 

  62. Chopra S, Liu J, Alemozaffar M, Nichols PW, Aron M, Weisenberger DJ, et al. Improving needle biopsy accuracy in small renal mass using tumor-specific DNA methylation markers. Oncotarget. 2017;8:5439–48.

    Article  PubMed  Google Scholar 

  63. Slater AA, Alokail M, Gentle D, Yao M, Kovacs G, Maher ER, et al. DNA methylation profiling distinguishes histological subtypes of renal cell carcinoma. Epigenetics. 2013;8:252–67.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  64. Malouf GG, Su X, Zhang J, Creighton CJ, Ho TH, Lu Y, et al. DNA methylation signature reveals cell ontogeny of renal cell carcinomas. Clin Cancer Res. 2016;22:6236–46.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  65. Ristau BT, Kutikov A, Uzzo RG, Smaldone MC. Active surveillance for small renal masses: when less is more. Eur Urol Focus. 2016;2:660–8.

    Article  PubMed  Google Scholar 

  66. Ravaud A, Motzer RJ, Pandha HS, George DJ, Pantuck AJ, Patel A, et al. Adjuvant sunitinib in high-risk renal-cell carcinoma after nephrectomy. N Engl J Med. 2016;375:2246–54.

    Article  PubMed  CAS  Google Scholar 

  67. Golovastova MO, Korolev DO, Tsoy LV, Varshavsky VA, Xu W-H, Vinarov AZ, et al. Biomarkers of renal tumors: the current state and clinical perspectives. Curr Urol Rep. 2017;18:3.

    Article  PubMed  Google Scholar 

  68. Golovastova MO, Tsoy LV, Bocharnikova AV, Korolev DO, Gancharova OS, Alekseeva EA, et al. The cancer-retina antigen recoverin as a potential biomarker for renal tumors. Tumour Biol. 2016;37:9899–907. https://doi.org/10.1007/s13277-016-4885-5.

    Article  PubMed  CAS  Google Scholar 

  69. Tezval H, Dubrowinskaja N, Peters I, Reese C, Serth K, Atschekzei F, et al. Tumor specific epigenetic silencing of corticotropin releasing hormone-binding protein in renal cell carcinoma: association of hypermethylation and metastasis. Castresana JS, editor. PLoS One. 2016;11:e0163873.

    Article  PubMed  PubMed Central  Google Scholar 

  70. Zhao H, Leppert JT, Peehl DM. A protective role for androgen receptor in clear cell renal cell carcinoma based on mining TCGA data. Chai KX, editor. PLoS One. 2016;11:e0146505.

    Article  PubMed  PubMed Central  Google Scholar 

  71. Mitsui Y, Hirata H, Arichi N, Hiraki M, Yasumoto H, Chang I, et al. Inactivation of bone morphogenetic protein 2 may predict clinical outcome and poor overall survival for renal cell carcinoma through epigenetic pathways. Oncotarget. 2015;6:9577–91.

    Article  PubMed  PubMed Central  Google Scholar 

  72. Deckers IAG, Schouten LJ, Van Neste L, van Vlodrop IJH, Soetekouw PMMB, Baldewijns MMLL, et al. Promoter methylation of CDO1 identifies clear-cell renal cell cancer patients with poor survival outcome. Clin Cancer Res. 2015;21:3492–500.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  73. Wang Z-R, Wei J-H, Zhou J-C, Haddad A, Zhao L-Y, Kapur P, et al. Validation of DAB2IP methylation and its relative significance in predicting outcome in renal cell carcinoma. Oncotarget Impact J. 2016;7:31508–19.

    Google Scholar 

  74. Pio Fabrizio F, Costantini M, Copetti M, la Torre A, Sparaneo A, Fontana A, et al. Keap1/Nrf2 pathway in kidney cancer: frequent methylation of KEAP1 gene promoter in clear renal cell carcinoma. Oncotarget. 2017;8:11187–98.

    Google Scholar 

  75. Brooks JD. Translational genomics: the challenge of developing cancer biomarkers. Genome Res. 2012;22:183–7. https://doi.org/10.1101/gr.124347.111.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  76. van Vlodrop IJH, Joosten SC, De Meyer T, Smits KM, Van Neste L, Melotte V, et al. A four-gene promoter methylation marker panel consisting of GREM1, NEURL, LAD1, and NEFH predicts survival of clear cell renal cell cancer patients. Clin Cancer Res. 2017;23:2006–18.

    Article  PubMed  Google Scholar 

  77. Evelönn EA, Degerman S, Köhn L, Landfors M, Ljungberg B, Roos G. DNA methylation status defines clinicopathological parameters including survival for patients with clear cell renal cell carcinoma (ccRCC). Tumor Biol. 2016;37:10219–28.

    Article  Google Scholar 

  78. Tian Y, Arai E, Gotoh M, Komiyama M, Fujimoto H, Kanai Y. Prognostication of patients with clear cell renal cell carcinomas based on quantification of DNA methylation levels of CpG island methylator phenotype marker genes. BMC Cancer. 2014;14:772.

    Article  PubMed  PubMed Central  Google Scholar 

  79. Arai E, Gotoh M, Tian Y, Sakamoto H, Ono M, Matsuda A, et al. Alterations of the spindle checkpoint pathway in clinicopathologically aggressive CpG island methylator phenotype clear cell renal cell carcinomas. Int J cancer. 2015;137:2589–606.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  80. Cancer Genome Atlas Research Network, Linehan WM, Spellman PT, Ricketts CJ, Creighton CJ, Fei SS, et al. Comprehensive molecular characterization of papillary renal-cell carcinoma. N Engl J Med. 2016;374:135–45.

    Article  Google Scholar 

  81. Xiao M, Yang H, Xu W, Ma S, Lin H, Zhu H, et al. Inhibition of -KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors. Genes Dev. 2012;26:1326–38.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  82. Chen K, Zhang J, Guo Z, Ma Q, Xu Z, Zhou Y, et al. Loss of 5-hydroxymethylcytosine is linked to gene body hypermethylation in kidney cancer. Cell Res. 2016;26:103–18.

    Article  PubMed  CAS  Google Scholar 

  83. Chen G, Wang Y, Wang L, Xu W. Identifying prognostic biomarkers based on aberrant DNA methylation in kidney renal clear cell carcinoma. Oncotarget. 2017;8:5268–80.

    PubMed  Google Scholar 

  84. Dimitrieva S, Schlapbach R, Rehrauer H. Prognostic value of cross-omics screening for kidney clear cell renal cancer survival. Biol Direct. 2016;11:68.

    Article  PubMed  PubMed Central  Google Scholar 

  85. Wei J-H, Haddad A, Wu K-J, Zhao H-W, Kapur P, Zhang Z-L, et al. A CpG-methylation-based assay to predict survival in clear cell renal cell carcinoma. Nat Commun. 2015;6:8699.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  86. Joosten SC, Deckers IA, Aarts MJ, Hoeben A, van Roermund JG, Smits KM, et al. Prognostic DNA methylation markers for renal cell carcinoma: a systematic review. Epigenomics. 2017;9(9):1243–57.

    Article  PubMed  CAS  Google Scholar 

  87. Choueiri TK, Fay AP, Gagnon R, Lin Y, Bahamon B, Brown V, et al. The role of aberrant VHL/HIF pathway elements in predicting clinical outcome to pazopanib therapy in patients with metastatic clear-cell renal cell carcinoma. Clin Cancer Res. 2013;19:5218–26. https://doi.org/10.1158/1078-0432.CCR-13-0491.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  88. Stewart GD, Powles T, Van Neste C, Meynert A, O’Mahony F, Laird A, et al. Dynamic epigenetic changes to VHL occur with sunitinib in metastatic clear cell renal cancer. Oncotarget Impact J. 2016;7:25241–50.

    Google Scholar 

  89. Peters I, Dubrowinskaja N, Abbas M, Seidel C, Kogosov M, Scherer R, et al. DNA methylation biomarkers predict progression-free and overall survival of metastatic renal cell cancer (mRCC) treated with antiangiogenic therapies. Zhang Z, editor. PLoS One. 2014;9:e91440. https://doi.org/10.1371/journal.pone.0091440.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  90. Dubrowinskaja N, Gebauer K, Peters I, Hennenlotter J, Abbas M, Scherer R, et al. Neurofilament heavy polypeptide CpG island methylation associates with prognosis of renal cell carcinoma and prediction of antivascular endothelial growth factor therapy response. Cancer Med. 2014;3:300–9. https://doi.org/10.1002/cam4.181.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  91. Wieczorek G, Asemissen A, Model F, Turbachova I, Floess S, Liebenberg V, et al. Quantitative DNA methylation analysis of FOXP3 as a new method for counting regulatory T cells in peripheral blood and solid tissue. Cancer Res. 2009;69:599–608. https://doi.org/10.1158/0008-5472.CAN-08-2361.

    Article  PubMed  CAS  Google Scholar 

  92. Schwarzer A, Wolf B, Fisher JL, Schwaab T, Olek S, Baron U, et al. Regulatory T-cells and associated pathways in metastatic renal cell carcinoma (mRCC) patients undergoing DC-vaccination and cytokine-therapy. Hoshino Y, editor. PLoS One. 2012;7:e46600. https://doi.org/10.1371/journal.pone.0046600.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  93. To KKW, Zhan Z, Bates SE. Aberrant promoter methylation of the ABCG2 gene in renal carcinoma. Mol Cell Biol. 2006;26:8572–85.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  94. Han T, Shang D, Xu X, Tian Y. Gene expression profiling of the synergy of 5-aza-2′-deoxycytidine and paclitaxel against renal cell carcinoma. World J Surg Oncol. 2012;10:183.

    Article  PubMed  PubMed Central  Google Scholar 

  95. Shang D, Liu Y, Xu X, Han T, Tian Y. 5-Aza-2′-deoxycytidine enhances susceptibility of renal cell carcinoma to paclitaxel by decreasing LEF1/phospho-β-catenin expression. Cancer Lett. 2011;311:230–6.

    Article  PubMed  CAS  Google Scholar 

  96. Liu Y, Zheng X, Yu Q, Wang H, Tan F, Zhu Q, et al. Epigenetic activation of the drug transporter OCT2 sensitizes renal cell carcinoma to oxaliplatin. Sci Transl Med. 2016;8:348ra97. https://doi.org/10.1126/scitranslmed.aaf3124.

    Article  PubMed  CAS  Google Scholar 

  97. Gollob JA, Sciambi CJ, Peterson BL, Richmond T, Thoreson M, Moran K, et al. Phase I trial of sequential low-dose 5-aza-2′-deoxycytidine plus high-dose intravenous bolus interleukin-2 in patients with melanoma or renal cell carcinoma. Clin Cancer Res Am Assoc Cancer Res. 2006;12:4619–27.

    Article  CAS  Google Scholar 

  98. Abele R, Clavel M, Dodion P, Bruntsch U, Gundersen S, Smyth J, et al. The EORTC Early Clinical Trials Cooperative Group experience with 5-aza-2′-deoxycytidine (NSC 127716) in patients with colorectal, head and neck, renal carcinomas and malignant melanomas. Eur J Cancer Clin Oncol. 1987;23:1921–4.

    Article  PubMed  CAS  Google Scholar 

  99. Shang D, Han T, Xu X, Liu Y. Decitabine induces G2/M cell cycle arrest by suppressing p38/NF-κB signaling in human renal clear cell carcinoma. Int J Clin Exp Pathol. 2015;8:11140–8.

    PubMed  PubMed Central  CAS  Google Scholar 

  100. Saleh MH, Wang L, Goldberg MS. Improving cancer immunotherapy with DNA methyltransferase inhibitors. Cancer Immunol Immunother. 2016;65:787–96.

    Article  PubMed  CAS  Google Scholar 

  101. Coral S, Sigalotti L, Altomonte M, Engelsberg A, Colizzi F, Cattarossi I, et al. 5-aza-2′-deoxycytidine-induced expression of functional cancer testis antigens in human renal cell carcinoma: immunotherapeutic implications. Clin Cancer Res. 2002;8:2690–5.

    PubMed  CAS  Google Scholar 

  102. Reu FJ, Bae SI, Cherkassky L, Leaman DW, Lindner D, Beaulieu N, et al. Overcoming resistance to interferon-induced apoptosis of renal carcinoma and melanoma cells by DNA demethylation. J Clin Oncol. 2006;24:3771–9. https://doi.org/10.1200/JCO.2005.03.4074.

    Article  PubMed  CAS  Google Scholar 

  103. Bhagat TD, Zou Y, Huang S, Park J, Palmer MB, Hu C, et al. Notch pathway is activated via genetic and epigenetic alterations and is a therapeutic target in clear cell renal cancer. J Biol Chem. 2017;292:837–46.

    Article  PubMed  CAS  Google Scholar 

  104. Hamilton E, Infante JR. Targeting CDK4/6 in patients with cancer. Cancer Treat Rev. 2016;45:129–38.

    Article  PubMed  CAS  Google Scholar 

  105. Motzer RJ, Escudier B, McDermott DF, George S, Hammers HJ, Srinivas S, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373:1803–13.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  106. Miao D, Margolis CA, Gao W, Voss MH, Li W, Martini DJ, et al. Genomic correlates of response to immune checkpoint therapies in clear cell renal cell carcinoma. Sci Am Assoc Adv Sci. 2018;359:801–6.

    CAS  Google Scholar 

  107. Bradley AJ, Lim YY, Singh FM. Imaging features, follow-up, and management of incidentally detected renal lesions. Clin Radiol. 2011;66:1129–39.

    Article  PubMed  CAS  Google Scholar 

  108. Gerlinger M, Rowan AJ, Horswell S, Larkin J, Endesfelder D, Gronroos E, et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med. 2012;366:883–92.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  109. Faleiro I, Leão R, Binnie A, de Mello RA, Maia A-T, Castelo-Branco P. Epigenetic therapy in urologic cancers: an update on clinical trials. Oncotarget Impact J. 2017;8:12484–500.

    Google Scholar 

  110. Day K, Waite LL, Thalacker-Mercer A, West A, Bamman MM, Brooks JD, et al. Differential DNA methylation with age displays both common and dynamic features across human tissues that are influenced by CpG landscape. Genome Biol. 2013;14:R102.

    Article  PubMed  PubMed Central  Google Scholar 

  111. Rius M, Lyko F. Epigenetic cancer therapy: rationales, targets and drugs. Oncog Nat Publ Group. 2012;31:4257–65.

    CAS  Google Scholar 

  112. Halby L, Champion C, Sénamaud-Beaufort C, Ajjan S, Drujon T, Rajavelu A, et al. Rapid synthesis of new DNMT inhibitors derivatives of procainamide. Chembiochem. 2012;13:157–65. https://doi.org/10.1002/cbic.201100522.

    Article  PubMed  CAS  Google Scholar 

  113. Lee BH, Yegnasubramanian S, Lin X, Nelson WG. Procainamide is a specific inhibitor of DNA methyltransferase 1. J Biol Chem. 2005;280:40749–56. https://doi.org/10.1074/jbc.M505593200.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. HudsonAlpha Institute for Biotechnology, 601 Genome Way, Huntsville, AL, 35806-2908, USA

    Brittany N. Lasseigne

  2. Department of Urology, Stanford University Medical Center, 300 Pasteur Drive, Stanford, CA, 94305-5118, USA

    James D. Brooks

Authors
  1. Brittany N. Lasseigne
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. James D. Brooks
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Brittany N. Lasseigne.

Ethics declarations

Conflict of interest

A patent is in process for the DNA methylation markers identified in the authors’ cited work: Lasseigne et al., BMC Medicine, 2014.

Funding

BNL was funded by the William J. Maier III Fellowship in Cancer Prevention (Prevent Cancer Foundation). JDB was funded by NIH/NCI (CA196387) and the Department of Defense (W81XWH-16-1-0553).

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lasseigne, B.N., Brooks, J.D. The Role of DNA Methylation in Renal Cell Carcinoma. Mol Diagn Ther 22, 431–442 (2018). https://doi.org/10.1007/s40291-018-0337-9

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40291-018-0337-9

Search

Navigation