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Departments of Surgical Oncology & Pathology, W350, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA

† Author for correspondence

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Email the corresponding author at paul.cairns@fccc.edu

Published Online:17 Feb 2011https://doi.org/10.2217/epi.10.64

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Abstract

This article focuses on the epigenetic alterations of aberrant promoter hypermethylation of genes, and histone modifications or RNA interference in cancer cells. Current knowledge of the hypermethylation of allele(s) in classical tumor suppressor genes in inherited and sporadic cancer, candidate tumor suppressor and other cancer genes is summarized gene by gene. Global and array-based studies of tumor cell hypermethylation are discussed. The importance of standardization of scoring of the methylation status of a gene is highlighted. The histone marks associated with hypermethylated genes, and the miRNAs with dysregulated expression, in kidney or bladder tumor cells are also discussed. Kidney cancer has the highest mortality rate of the genito–urinary cancers. There are management issues associated with the high recurrence rate of superficial bladder cancer, while muscle-invasive bladder cancer has a poor prognosis. These clinical problems are the basis for the translational application of gene hypermethylation in the diagnosis and prognosis of kidney and bladder cancer.

Keywords:

Papers of special note have been highlighted as: ▪ of interest

Bibliography

1 Jemal A, Siegel R, Xu J, Ward E: Cancer statistics, 2010. CA Cancer J. Clin.60,277–300 (2010).
MedlineGoogle Scholar
2 Cohen HT, McGovern FJ: Renal-cell carcinoma. N. Engl. J. Med.353,2477–2490 (2005).
Medline CASGoogle Scholar
3 Zambrano NR, Lubensky IA, Merino MJ, Linehan WM, Walther MM: Histopathology and molecular genetics of renal tumors: toward unification of a classification system. J. Urol.162,1246–1258 (1999).
Medline CASGoogle Scholar
4 Herr H, Lamm DL, Denis L: Management of superficial bladder cancer. In: Principles & Practice of Genitourinary Oncology. Raghavan D, Scher HL, Leibel SA, Lange PH (Eds). Lippincott-Raven, PA, USA, 273–280 (1997).
Google Scholar
5 Cairns P, Sidransky D: Bladder Cancer, 2nd Edition. New York McGraw-Hill, NY, USA (2002).
Google Scholar
6 Dalgliesh GL, Furge K, Greenman C et al.: Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes. Nature463,360–363 (2010).
Medline CASGoogle Scholar
7 Thomas RK, Baker AC, Debiasi RM et al.: High-throughput oncogene mutation profiling in human cancer. Nat. Genet.39,347–351 (2007).
Medline CASGoogle Scholar
8 Beroukhim R, Brunet JP, Di Napoli A et al.: Patterns of gene expression and copy-number alterations in von-Hippel Lindau disease-associated and sporadic clear cell carcinoma of the kidney. Cancer Res.69,4674–4681 (2009).
Medline CASGoogle Scholar
9 Hoque MO, Lee CC, Cairns P, Schoenberg M, Sidransky D: Genome-wide genetic characterization of bladder cancer: a comparison of high-density single-nucleotide polymorphism arrays and PCR-based microsatellite analysis. Cancer Res.63,2216–2222 (2003).
Medline CASGoogle Scholar
10 Jones PA, Baylin SB: The fundamental role of epigenetic events in cancer. Nat. Rev. Genet.3,415–428 (2002).
Medline CASGoogle Scholar
11 Dunn BK: Hypomethylation: one side of a larger picture. Ann. NY Acad. Sci.983,28–42 (2003).
Medline CASGoogle Scholar
12 Cui H, Niemitz EL, Ravenel JD et al.: Loss of imprinting of insulin-like growth factor-II in Wilms’ tumor commonly involves altered methylation but not mutations of CTCF or its binding site. Cancer Res.61,4947–4950 (2001).
Medline CASGoogle Scholar
13 Cui H, Onyango P, Brandenburg S, Wu Y, Hsieh CL, Feinberg AP: Loss of imprinting in colorectal cancer linked to hypomethylation of H19 and IGF2. Cancer Res.62,6442–6446 (2002).
Medline CASGoogle Scholar
14 Byun HM, Wong HL, Birnstein EA, Wolff EM, Liang G, Yang AS: Examination of IGF2 and H19 loss of imprinting in bladder cancer. Cancer Res.67,10753–10758 (2007).
Medline CASGoogle Scholar
15 Herman JG, Latif F, Weng Y et al.: Silencing of the VHL tumor-suppressor gene by DNA methylation in renal carcinoma. Proc. Natl Acad. Sci. USA91,9700–9704 (1994).
Medline CASGoogle Scholar
16 Dulaimi E, Ibanez de Caceres I, Uzzo RG et al.: Promoter hypermethylation profile of kidney cancer. Clin. Cancer Res.10,3972–3979 (2004).
Medline CASGoogle Scholar
17 Schmidt L, Duh FM, Chen F et al.: Germline and somatic mutations in the tyrosine kinase domain of the MET proto-oncogene in papillary renal carcinomas. Nat. Genet.16,68–73 (1997).
Medline CASGoogle Scholar
18 Tomlinson IP, Alam NA, Rowan AJ et al.: Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer. Nat. Genet.30,406–410 (2002).
Medline CASGoogle Scholar
19 Nickerson ML, Warren MB, Toro JR et al.: Mutations in a novel gene lead to kidney tumors, lung wall defects, and benign tumors of the hair follicle in patients with the Birt–Hogg–Dube syndrome. Cancer Cell2,157–164 (2002).
Medline CASGoogle Scholar
20 da Silva NF, Gentle D, Hesson LB, Morton DG, Latif F, Maher ER: Analysis of the Birt–Hogg–Dube (BHD) tumour suppressor gene in sporadic renal cell carcinoma and colorectal cancer. J. Med. Genet.40,820–824 (2003).
Medline CASGoogle Scholar
21 Gad S, Lefevre SH, Khoo SK et al.: Mutations in BHD and TP53 genes, but not in HNF1β gene, in a large series of sporadic chromophobe renal cell carcinoma. Br. J. Cancer96,336–340 (2007).
Medline CASGoogle Scholar
22 Ricketts C, Woodward ER, Killick P et al.: Germline SDHB mutations and familial renal cell carcinoma. J. Natl Cancer Inst.100,1260–1262 (2008).
Medline CASGoogle Scholar
23 Morris MR, Hesson LB, Wagner KJ et al.: Multigene methylation analysis of Wilms’ tumour and adult renal cell carcinoma. Oncogene22,6794–6801 (2003).
Medline CASGoogle Scholar
24 Lynch HT, Smyrk TC, Watson P et al.: Genetics, natural history, tumor spectrum, and pathology of hereditary nonpolyposis colorectal cancer: an updated review. Gastroenterology104,1535–1549 (1993).
Medline CASGoogle Scholar
25 Gylling AH, Nieminen TT, Abdel-Rahman WM et al.: Differential cancer predisposition in Lynch syndrome: insights from molecular analysis of brain and urinary tract tumors. Carcinogenesis29,1351–1359 (2008).
Medline CASGoogle Scholar
26 Herman JG, Umar A, Polyak K et al.: Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma. Proc. Natl Acad. Sci. USA95,6870–6875 (1998).
Medline CASGoogle Scholar
27 Catto JW, Azzouzi AR, Rehman I et al.: Promoter hypermethylation is associated with tumor location, stage, and subsequent progression in transitional cell carcinoma. J. Clin. Oncol.23,2903–2910 (2005).
Medline CASGoogle Scholar
28 Esteller M, Levine R, Baylin SB, Ellenson LH, Herman JG: MLH1 promoter hypermethylation is associated with the microsatellite instability phenotype in sporadic endometrial carcinomas. Oncogene17,2413–2417 (1998).
Medline CASGoogle Scholar
29 Esteller M, Catasus L, Matias-Guiu X et al.: hMLH1 promoter hypermethylation is an early event in human endometrial tumorigenesis. Am. J. Pathol.155,1767–1772 (1999).
Medline CASGoogle Scholar
30 Haibach H, Burns TW, Carlson HE, Burman KD, Deftos LJ: Multiple hamartoma syndrome (Cowden’s disease) associated with renal cell carcinoma and primary neuroendocrine carcinoma of the skin (Merkel cell carcinoma). Am. J. Clin. Pathol.97,705–712 (1992).
Medline CASGoogle Scholar
31 Pilarski R, Eng C: Will the real Cowden syndrome please stand up (again)? Expanding mutational and clinical spectra of the PTEN hamartoma tumour syndrome. J. Med. Genet.41,323–326 (2004).
Medline CASGoogle Scholar
32 Liaw D, Marsh DJ, Li J et al.: Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome. Nat. Genet.16,64–67 (1997).
Medline CASGoogle Scholar
33 Cairns P, Evron E, Okami K et al.: Point mutation and homozygous deletion of PTEN/MMAC1 in primary bladder cancers. Oncogene16,3215–3218 (1998).
Medline CASGoogle Scholar
34 Zysman MA, Chapman WB, Bapat B: Considerations when analyzing the methylation status of PTEN tumor suppressor gene. Am. J. Pathol.160,795–800 (2002).
Medline CASGoogle Scholar
35 Niida Y, Stemmer-Rachamimov AO, Logrip M et al.: Survey of somatic mutations in tuberous sclerosis complex (TSC) hamartomas suggests different genetic mechanisms for pathogenesis of TSC lesions. Am. J. Hum. Genet.69,493–503 (2001).
Medline CASGoogle Scholar
36 Rocco JW, Sidransky D: p16(MTS-1/CDKN2/INK4a) in cancer progression. Exp. Cell Res.264,42–55 (2001).
Medline CASGoogle Scholar
37 Herman JG, Merlo A, Mao L et al.: Inactivation of the CDKN2/p16/MTS1 gene is frequently associated with aberrant DNA methylation in all common human cancers. Cancer Res.55,4525–4530 (1995).
Medline CASGoogle Scholar
38 Smiraglia DJ, Rush LJ, Fruhwald MC et al.: Excessive CpG island hypermethylation in cancer cell lines versus primary human malignancies. Hum. Mol. Genet.10,1413–1419 (2001).▪ Illustrates the point that tumor cell lines need not be representative of the extent of aberrant methylation in a primary tumor.
Medline CASGoogle Scholar
39 Dulaimi E, Uzzo RG, Greenberg RE, Al-Saleem T, Cairns P: Detection of bladder cancer in urine by a tumor suppressor gene hypermethylation panel. Clin. Cancer Res.10,1887–1893 (2004).
Medline CASGoogle Scholar
40 Robertson KD, Jones PA: The human ARF cell cycle regulatory gene promoter is a CpG island which can be silenced by DNA methylation and down-regulated by wild-type p53. Mol. Cell Biol.18,6457–6473 (1998).
Medline CASGoogle Scholar
41 Esteller M, Corn PG, Baylin SB, Herman JG: A gene hypermethylation profile of human cancer. Cancer Res.61,3225–3229 (2001).
Medline CASGoogle Scholar
42 Esteller M, Sparks A, Toyota M et al.: Analysis of adenomatous polyposis coli promoter hypermethylation in human cancer. Cancer Res.60,4366–4371 (2000).
Medline CASGoogle Scholar
43 Maruyama R, Toyooka S, Toyooka KO et al.: Aberrant promoter methylation profile of bladder cancer and its relationship to clinicopathological features. Cancer Res.61,8659–8663 (2001).
Medline CASGoogle Scholar
44 Neuhausen A, Florl AR, Grimm MO, Schulz WA: DNA methylation alterations in urothelial carcinoma. Cancer Biol. Ther.5,993–1001 (2006).
Medline CASGoogle Scholar
45 Becker KF, Atkinson MJ, Reich U et al.: E-cadherin gene mutations provide clues to diffuse type gastric carcinomas. Cancer Res.54,3845–3852 (1994).
Medline CASGoogle Scholar
46 Guilford P, Hopkins J, Harraway J et al.: E-cadherin germline mutations in familial gastric cancer. Nature392,402–405 (1998).
Medline CASGoogle Scholar
47 Grady WM, Willis J, Guilford PJ et al.: Methylation of the CDH1 promoter as the second genetic hit in hereditary diffuse gastric cancer. Nat. Genet.26,16–17 (2000).
Medline CASGoogle Scholar
48 Kawakami T, Okamoto K, Ogawa O, Okada Y: Multipoint methylation and expression analysis of tumor suppressor genes in human renal cancer cells. Urology61,226–230 (2003).
MedlineGoogle Scholar
49 Chung WB, Hong SH, Kim JA, Sohn YK, Kim BW, Kim JW: Hypermethylation of tumor-related genes in genitourinary cancer cell lines. J. Korean Med. Sci.16,756–761 (2001).
Medline CASGoogle Scholar
50 Ribeiro-Filho LA, Franks J, Sasaki M et al.: CpG hypermethylation of promoter region and inactivation of E-cadherin gene in human bladder cancer. Mol. Carcinog.34,187–198 (2002).
Medline CASGoogle Scholar
51 Reinhold WC, Reimers MA, Maunakea AK et al.: Detailed DNA methylation profiles of the E-cadherin promoter in the NCI-60 cancer cells. Mol. Cancer Ther.6,391–403 (2007).▪ Detailed study across the promoter region of E-cadherin revealed significant differences in methylation between individual CpG sites in the same tumor cell line and between different tumor cell lines in the National Cancer Institute-60 panel, and defines a threshold of approximately 20–30% of promoter CpG sites methylated, necessary for silencing of mRNA expression.
Medline CASGoogle Scholar
52 Stirzaker C, Millar DS, Paul CL et al.: Extensive DNA methylation spanning the Rb promoter in retinoblastoma tumors. Cancer Res.57,2229–2237 (1997).
Medline CASGoogle Scholar
53 Bachman KE, Herman JG, Corn PG et al.: Methylation-associated silencing of the tissue inhibitor of metalloproteinase-3 gene suggest a suppressor role in kidney, brain, and other human cancers. Cancer Res.59,798–802 (1999).
Medline CASGoogle Scholar
54 Kagan J, Srivastava S, Barker PE, Belinsky SA, Cairns P: Towards clinical application of methylated DNA sequences as cancer biomarkers: a joint NCI’s EDRN and NIST workshop on standards, methods, assays, reagents and tools. Cancer Res.67,4545–4549 (2007).
Medline CASGoogle Scholar
55 Dammann R, Li C, Yoon JH, Chin PL, Bates S, Pfeifer GP: Epigenetic inactivation of a RAS association domain family protein from the lung tumour suppressor locus 3p21.3. Nat. Genet.25,315–319 (2000).
Medline CASGoogle Scholar
56 Dreijerink K, Braga E, Kuzmin I et al.: The candidate tumor suppressor gene, RASSF1A, from human chromosome 3p21.3 is involved in kidney tumorigenesis. Proc. Natl Acad. Sci. USA98,7504–7509 (2001).
Medline CASGoogle Scholar
57 Morrissey C, Martinez A, Zatyka M et al.: Epigenetic inactivation of the RASSF1A 3p21.3 tumor suppressor gene in both clear cell and papillary renal cell carcinoma. Cancer Res.61,7277–7281 (2001).
Medline CASGoogle Scholar
58 Yoon JH, Dammann R, Pfeifer GP: Hypermethylation of the CpG island of the RASSF1A gene in ovarian and renal cell carcinomas. Int. J. Cancer94,212–217 (2001).▪ The above four publications are important because they reported aberrant hyperemethylation of a gene to be frequent and across different tumor types.
Medline CASGoogle Scholar
59 Chan MW, Chan LW, Tang NL et al.: Frequent hypermethylation of promoter region of RASSF1A in tumor tissues and voided urine of urinary bladder cancer patients. Int. J. Cancer104,611–616 (2003).
Medline CASGoogle Scholar
60 Lee MG, Kim HY, Byun DS et al.: Frequent epigenetic inactivation of RASSF1A in human bladder carcinoma. Cancer Res.61,6688–6692 (2001).
Medline CASGoogle Scholar
61 Lee WH, Morton RA, Epstein JI et al.: Cytidine methylation of regulatory sequences near the πι-class glutathione S-transferase gene accompanies human prostatic carcinogenesis. Proc. Natl Acad. Sci. USA91,11733–11737 (1994).
Medline CASGoogle Scholar
62 Chan MW, Chan LW, Tang NL et al.: Hypermethylation of multiple genes in tumor tissues and voided urine in urinary bladder cancer patients. Clin. Cancer Res.8,464–470 (2002).
Medline CASGoogle Scholar
63 Esteller M, Corn PG, Urena JM, Gabrielson E, Baylin SB, Herman JG: Inactivation of glutathione S-transferase P1 gene by promoter hypermethylation in human neoplasia. Cancer Res.58,4515–4518 (1998).
Medline CASGoogle Scholar
64 Esteller M, Hamilton SR, Burger PC, Baylin SB, Herman JG: Inactivation of the DNA repair gene O6-methylguanine-DNA methyltransferase by promoter hypermethylation is a common event in primary human neoplasia. Cancer Res.59,793–797 (1999).
Medline CASGoogle Scholar
65 Hoque MO, Begum S, Topaloglu O et al.: Quantitative detection of promoter hypermethylation of multiple genes in the tumor, urine, and serum DNA of patients with renal cancer. Cancer Res.64,5511–5517 (2004).
Medline CASGoogle Scholar
66 Kissil JL, Feinstein E, Cohen O et al.: DAP-kinase loss of expression in various carcinoma and B-cell lymphoma cell lines: possible implications for role as tumor suppressor gene. Oncogene15,403–407 (1997).
Medline CASGoogle Scholar
67 Katzenellenbogen RA, Baylin SB, Herman JG: Hypermethylation of the DAP-kinase CpG island is a common alteration in B-cell malignancies. Blood93,4347–4353 (1999).
Medline CASGoogle Scholar
68 Gonzalgo ML, Yegnasubramanian S, Yan G et al.: Molecular profiling and classification of sporadic renal cell carcinoma by quantitative methylation analysis. Clin. Cancer Res.10,7276–7283 (2004).
Medline CASGoogle Scholar
69 Wethkamp N, Ramp U, Geddert H et al.: Expression of death-associated protein kinase during tumour progression of human renal cell carcinomas: hypermethylation-independent mechanisms of inactivation. Eur. J. Cancer42,264–274 (2006).
Medline CASGoogle Scholar
70 Tada Y, Wada M, Taguchi K et al.: The association of death-associated protein kinase hypermethylation with early recurrence in superficial bladder cancers. Cancer Res.62,4048–4053 (2002).
Medline CASGoogle Scholar
71 Christoph F, Kempkensteffen C, Weikert S et al.: Methylation of tumour suppressor genes APAF-1 and DAPK-1 and in vitro effects of demethylating agents in bladder and kidney cancer. Br. J. Cancer95,1701–1707 (2006).
Medline CASGoogle Scholar
72 Marsit CJ, Houseman EA, Christensen BC et al.: Examination of a CpG island methylator phenotype and implications of methylation profiles in solid tumors. Cancer Res.66,10621–10629 (2006).
Medline CASGoogle Scholar
73 Sathyanarayana UG, Maruyama R, Padar A et al.: Molecular detection of noninvasive and invasive bladder tumor tissues and exfoliated cells by aberrant promoter methylation of laminin-5 encoding genes. Cancer Res.64,1425–1430 (2004).
Medline CASGoogle Scholar
74 Takahashi T, Suzuki M, Shigematsu H et al.: Aberrant methylation of Reprimo in human malignancies. Int. J. Cancer115,503–510 (2005).
Medline CASGoogle Scholar
75 Iliopoulos D, Guler G, Han SY et al.: Fragile genes as biomarkers: epigenetic control of WWOX and FHIT in lung, breast and bladder cancer. Oncogene24,1625–1633 (2005).
Medline CASGoogle Scholar
76 Kvasha S, Gordiyuk V, Kondratov A et al.: Hypermethylation of the 5´CpG island of the FHIT gene in clear cell renal carcinomas. Cancer Lett.265,250–257 (2008).
Medline CASGoogle Scholar
77 Morris MR, Gentle D, Abdulrahman M et al.: Tumor suppressor activity and epigenetic inactivation of hepatocyte growth factor activator inhibitor type 2/SPINT2 in papillary and clear cell renal cell carcinoma. Cancer Res.65,4598–4606 (2005).
Medline CASGoogle Scholar
78 Agathanggelou A, Dallol A, Zochbauer-Muller S et al.: Epigenetic inactivation of the candidate 3p21.3 suppressor gene BLU in human cancers. Oncogene22,1580–1588 (2003).
Medline CASGoogle Scholar
79 Stoehr R, Wissmann C, Suzuki H et al.: Deletions of chromosome 8p and loss of sFRP1 expression are progression markers of papillary bladder cancer. Lab. Invest.84,465–478 (2004).
Medline CASGoogle Scholar
80 Marsit CJ, Karagas MR, Andrew A et al.: Epigenetic inactivation of SFRP genes and TP53 alteration act jointly as markers of invasive bladder cancer. Cancer Res.65,7081–7085 (2005).
Medline CASGoogle Scholar
81 Dahl E, Wiesmann F, Woenckhaus M et al.: Frequent loss of SFRP1 expression in multiple human solid tumours: association with aberrant promoter methylation in renal cell carcinoma. Oncogene26,5680–5691 (2007).
Medline CASGoogle Scholar
82 Kagara I, Enokida H, Kawakami K et al.: CpG hypermethylation of the UCHL1 gene promoter is associated with pathogenesis and poor prognosis in renal cell carcinoma. J. Urol.180,343–351 (2008).
Medline CASGoogle Scholar
83 Urakami S, Shiina H, Enokida H et al.: Combination analysis of hypermethylated Wnt-antagonist family genes as a novel epigenetic biomarker panel for bladder cancer detection. Clin. Cancer Res.12,2109–2116 (2006).
Medline CASGoogle Scholar
84 de Caestecker MP, Piek E, Roberts AB: Role of transforming growth factor-β signaling in cancer. J. Natl Cancer Inst.92,1388–1402 (2000).
Medline CASGoogle Scholar
85 Roberts AB, Wakefield LM: The two faces of transforming growth factor β in carcinogenesis. Proc. Natl Acad. Sci. USA100,8621–8623 (2003).
Medline CASGoogle Scholar
86 Teicher BA: Malignant cells, directors of the malignant process: role of transforming growth factor-β. Cancer Metastasis Rev.20,133–143 (2001).
Medline CASGoogle Scholar
87 Suzuki M, Shigematsu H, Shames DS et al.: DNA methylation-associated inactivation of TGFβ-related genes DRM/Gremlin, RUNX3, and HPP1 in human cancers. Br. J. Cancer93,1029–1037 (2005).
Medline CASGoogle Scholar
88 Okuda H, Toyota M, Ishida W et al.: Epigenetic inactivation of the candidate tumor suppressor gene HOXB13 in human renal cell carcinoma. Oncogene25,1733–1742 (2006).
Medline CASGoogle Scholar
89 Yamada D, Kikuchi S, Williams YN et al.: Promoter hypermethylation of the potential tumor suppressor DAL-1/4.1B gene in renal clear cell carcinoma. Int. J. Cancer118,916–923 (2006).
Medline CASGoogle Scholar
90 To KK, Zhan Z, Bates SE: Aberrant promoter methylation of the ABCG2 gene in renal carcinoma. Mol. Cell Biol.26,8572–8585 (2006).
Medline CASGoogle Scholar
91 Kawakami T, Chano T, Minami K, Okabe H, Okada Y, Okamoto K: Imprinted DLK1 is a putative tumor suppressor gene and inactivated by epimutation at the region upstream of GTL2 in human renal cell carcinoma. Hum. Mol. Genet.15,821–830 (2006).
Medline CASGoogle Scholar
92 Reu FJ, Bae SI, Cherkassky L et al.: Overcoming resistance to interferon-induced apoptosis of renal carcinoma and melanoma cells by DNA demethylation. J. Clin. Oncol.24,3771–3779 (2006).
Medline CASGoogle Scholar
93 Lee MG, Huh JS, Chung SK et al.: Promoter CpG hypermethylation and downregulation of XAF1 expression in human urogenital malignancies: implication for attenuated p53 response to apoptotic stresses. Oncogene25,5807–5822 (2006).
Medline CASGoogle Scholar
94 Kempkensteffen C, Hinz S, Schrader M et al.: Gene expression and promoter methylation of the XIAP-associated factor 1 in renal cell carcinomas: correlations with pathology and outcome. Cancer Lett.254,227–235 (2007).
Medline CASGoogle Scholar
95 Ibanez de Caceres I, Dulaimi E, Hoffman AM, Al-Saleem T, Uzzo RG, Cairns P: Identification of novel target genes by an epigenetic reactivation screen of renal cancer. Cancer Res.66,5021–5028 (2006).
Medline CASGoogle Scholar
96 Agathanggelou A, Bieche I, Ahmed-Choudhury J et al.: Identification of novel gene expression targets for the Ras association domain family 1 (RASSF1A) tumor suppressor gene in non-small-cell lung cancer and neuroblastoma. Cancer Res.63,5344–5351 (2003).
Medline CASGoogle Scholar
97 Mori K, Enokida H, Kagara I et al.: CpG hypermethylation of collagen type I a2 contributes to proliferation and migration activity of human bladder cancer. Int. J. Oncol.34,1593–1602 (2009).
Medline CASGoogle Scholar
98 Liang G, Gonzales FA, Jones PA, Orntoft TF, Thykjaer T: Analysis of gene induction in human fibroblasts and bladder cancer cells exposed to the methylation inhibitor 5-aza-2´-deoxycytidine. Cancer Res.62,961–966 (2002).▪ First use of a genome-wide expresssion array after demethylating drug treatment of a tumor cell line as a global discovery tool.
Medline CASGoogle Scholar
99 Suzuki H, Gabrielson E, Chen W et al.: A genomic screen for genes upregulated by demethylation and histone deacetylase inhibition in human colorectal cancer. Nat. Genet.31,141–149 (2002).
Medline CASGoogle Scholar
100 Morris MR, Gentle D, Abdulrahman M et al.: Functional epigenomics approach to identify methylated candidate tumour suppressor genes in renal cell carcinoma. Br. J. Cancer98,496–501 (2008).
Medline CASGoogle Scholar
101 Morris MR, Ricketts C, Gentle D et al.: Identification of candidate tumour suppressor genes frequently methylated in renal cell carcinoma. Oncogene29,2104–2117 (2010).
Medline CASGoogle Scholar
102 Seliger B, Handke D, Schabel E, Bukur J, Lichtenfels R, Dammann R: Epigenetic control of the ubiquitin carboxyl terminal hydrolase 1 in renal cell carcinoma. J. Transl. Med.7,90 (2009).
MedlineGoogle Scholar
103 Dalgin GS, Drever M, Williams T, King T, DeLisi C, Liou LS: Identification of novel epigenetic markers for clear cell renal cell carcinoma. J. Urol.180,1126–1130 (2008).
Medline CASGoogle Scholar
104 McRonald FE, Morris MR, Gentle D et al.: CpG methylation profiling in VHL related and VHL unrelated renal cell carcinoma. Mol. Cancer8,31 (2009).▪ First report of Illumina® (CA, USA) BeadChip methylation technology in renal cancer.
MedlineGoogle Scholar
105 Wu G, Guo Z, Chang X et al.: LOXL1 and LOXL4 are epigenetically silenced and can inhibit ras/extracellular signal-regulated kinase signaling pathway in human bladder cancer. Cancer Res.67,4123–4129 (2007).
Medline CASGoogle Scholar
106 Veerla S, Panagopoulos I, Jin Y, Lindgren D, Hoglund M: Promoter analysis of epigenetically controlled genes in bladder cancer. Genes Chromosomes Cancer47,368–378 (2008).
Medline CASGoogle Scholar
107 Cairns P: Gene methylation and early detection of genitourinary cancer: the road ahead. Nat. Rev. Cancer7,531–543 (2007).▪ Discussion of the promise and challenges of aberrant methylation for early detection of cancer.
Medline CASGoogle Scholar
108 Teodoridis JM, Hardie C, Brown R: CpG island methylator phenotype (CIMP) in cancer: causes and implications. Cancer Lett.268,177–186 (2008).
Medline CASGoogle Scholar
109 Zhang L, Yu J, Willson JK, Markowitz SD, Kinzler KW, Vogelstein B: Short mononucleotide repeat sequence variability in mismatch repair-deficient cancers. Cancer Res.61,3801–3805 (2001).
Medline CASGoogle Scholar
110 Esteller M: Epigenetics in cancer. N. Engl. J. Med.358,1148–1159 (2008).
Medline CASGoogle Scholar
111 Nguyen CT, Weisenberger DJ, Velicescu M et al.: Histone H3-lysine 9 methylation is associated with aberrant gene silencing in cancer cells and is rapidly reversed by 5-aza-2´-deoxycytidine. Cancer Res.62,6456–6461 (2002).
Medline CASGoogle Scholar
112 Fraga MF, Ballestar E, Villar-Garea A et al.: Loss of acetylation at Lys16 and trimethylation at Lys20 of histone H4 is a common hallmark of human cancer. Nat. Genet.37,391–400 (2005).
Medline CASGoogle Scholar
113 Ozdag H, Teschendorff AE, Ahmed AA et al.: Differential expression of selected histone modifier genes in human solid cancers. BMC Genomics7,90 (2006).
MedlineGoogle Scholar
114 Stransky N, Vallot C, Reyal F et al.: Regional copy number-independent deregulation of transcription in cancer. Nat. Genet.38,1386–1396 (2006).
Medline CASGoogle Scholar
115 Seligson DB, Horvath S, McBrian MA et al.: Global levels of histone modifications predict prognosis in different cancers. Am. J. Pathol.174,1619–1628 (2009).
Medline CASGoogle Scholar
116 Ellinger J, Kahl P, Mertens C et al.: Prognostic relevance of global histone H3 lysine 4 (H3K4) methylation in renal cell carcinoma. Int. J. Cancer127,2360–2366 (2010).
Medline CASGoogle Scholar
117 Lamy P, Andersen CL, Dyrskjot L, Torring N, Orntoft T, Wiuf C: Are microRNAs located in genomic regions associated with cancer? Br. J. Cancer95,1415–1418 (2006).
Medline CASGoogle Scholar
118 Saito Y, Jones PA: Epigenetic activation of tumor suppressor microRNAs in human cancer cells. Cell Cycle5,2220–2222 (2006).
Medline CASGoogle Scholar
119 Friedman JM, Liang G, Liu CC et al.: The putative tumor suppressor microRNA-101 modulates the cancer epigenome by repressing the polycomb group protein EZH2. Cancer Res.69,2623–2629 (2009).
Medline CASGoogle Scholar
120 Catto JW, Miah S, Owen HC et al.: Distinct microRNA alterations characterize high- and low-grade bladder cancer. Cancer Res.69,8472–8481 (2009).
Medline CASGoogle Scholar
121 Dyrskjot L, Ostenfeld MS, Bramsen JB et al.: Genomic profiling of microRNAs in bladder cancer: miR-129 is associated with poor outcome and promotes cell death in vitro. Cancer Res.69,4851–4860 (2009).
Medline CASGoogle Scholar
122 Wiklund ED, Bramsen JB, Hulf T et al.: Coordinated epigenetic repression of the miR-200 family and miR-205 in invasive bladder cancer. Int. J. Cancer (2010) (Epub ahead of print).
MedlineGoogle Scholar
123 Jung M, Mollenkopf HJ, Grimm C et al.: MicroRNA profiling of clear cell renal cell cancer identifies a robust signature to define renal malignancy. J. Cell. Mol. Med.13,3918–3928 (2009).
MedlineGoogle Scholar
124 Nakada C, Matsuura K, Tsukamoto Y et al.: Genome-wide microRNA expression profiling in renal cell carcinoma: significant down-regulation of miR-141 and miR-200c. J. Pathol.216,418–427 (2008).
Medline CASGoogle Scholar
125 Juan D, Alexe G, Antes T et al.: Identification of a microRNA panel for clear-cell kidney cancer. Urology75(4),835–841 (2010).
MedlineGoogle Scholar
126 Banumathy G, Cairns P: Signaling pathways in renal cell carcinoma. Cancer Biol. Ther.10(7),658–664 (2010).
Medline CASGoogle Scholar
127 Battagli C, Uzzo RG, Dulaimi E et al.: Promoter hypermethylation of tumor suppressor genes in urine from kidney cancer patients. Cancer Res.63,8695–8699 (2003).
Medline CASGoogle Scholar
128 Friedrich MG, Weisenberger DJ, Cheng JC et al.: Detection of methylated apoptosis-associated genes in urine sediments of bladder cancer patients. Clin. Cancer Res.10,7457–7465 (2004).
Medline CASGoogle Scholar
129 Hoque MO, Begum S, Topaloglu O et al.: Quantitation of promoter methylation of multiple genes in urine DNA and bladder cancer detection. J. Natl Cancer Inst.98,996–1004 (2006).
Medline CASGoogle Scholar
130 Yates DR, Rehman I, Meuth M, Cross SS, Hamdy FC, Catto JW: Methylational urinalysis: a prospective study of bladder cancer patients and age stratified benign controls. Oncogene25,1984–1988 (2006).
Medline CASGoogle Scholar
131 Renard I, Joniau S, van Cleynenbreugel B et al.: Identification and validation of the methylated TWIST1 and NID2 genes through real-time methylation-specific polymerase chain reaction assays for the noninvasive detection of primary bladder cancer in urine samples. Eur. Urol.58(1),96–104 (2009).
MedlineGoogle Scholar
132 Costa VL, Henrique R, Ribeiro FR et al.: Quantitative promoter methylation analysis of multiple cancer-related genes in renal cell tumors. BMC Cancer7,133 (2007).
MedlineGoogle Scholar
133 Gutierrez MI, Siraj AK, Khaled H, Koon N, El-Rifai W, Bhatia K: CpG island methylation in schistosoma- and non-schistosoma-associated bladder cancer. Mod. Pathol.17,1268–1274 (2004).
Medline CASGoogle Scholar
134 Breault JE, Shiina H, Igawa M et al.: Methylation of the γ-catenin gene is associated with poor prognosis of renal cell carcinoma. Clin. Cancer Res.11,557–564 (2005).
Medline CASGoogle Scholar
135 Yates DR, Rehman I, Abbod MF et al.: Promoter hypermethylation identifies progression risk in bladder cancer. Clin. Cancer Res.13,2046–2053 (2007).
Medline CASGoogle Scholar
136 Gollob JA, Sciambi CJ, Peterson BL 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.12,4619–4627 (2006).
Medline CASGoogle Scholar
137 Winquist E, Knox J, Ayoub JP et al.: Phase II trial of DNA methyltransferase 1 inhibition with the antisense oligonucleotide MG98 in patients with metastatic renal carcinoma: a National Cancer Institute of Canada Clinical Trials Group investigational new drug study. Invest. New Drugs24,159–167 (2006).
Medline CASGoogle Scholar
138 Hammers HJ, Verheul H, Wilky B et al.: Phase I safety and pharmacokinetic/pharmacodynamic results of the histone deacetylase inhibitor vorinostat in combination with bevacizumab in patients with kidney cancer. J. Clin. Oncol.26, (2008) (Abstract 16094).
Google Scholar
139 Verheul HM, Salumbides B, van Erp K et al.: Combination strategy targeting the hypoxia inducible factor-1 α with mammalian target of rapamycin and histone deacetylase inhibitors. Clin. Cancer Res.14,3589–3597 (2008).
Medline CASGoogle Scholar
140 Shang D, Liu Y, Matsui Y et al.: Demethylating agent 5-aza-2´-deoxycytidine enhances susceptibility of bladder transitional cell carcinoma to cisplatin. Urology71,1220–1225 (2008).
MedlineGoogle Scholar
141 Costello JF, Frühwald MC, Smiraglia DJ et al.: Aberrant CpG-island methylation has non-random and tumour-type-specific patterns. Nature Genet.25,132–138 (2000).
MedlineGoogle Scholar
142 Sjoblom T, Jones S, Wood LD et al.: The consensus coding sequences of human breast and colorectal cancers. Science314,268–274 (2006).
MedlineGoogle Scholar
143 Aleman A, Cebrian V, Alvarez M et al.: Identification of PMF1 methylation in association with bladder cancer progression. Clin. Cancer Res.14,8236–8243 (2008).
Medline CASGoogle Scholar
144 Kwabi-Addo B, Chung W, Shen L et al.: Age-related DNA methylation changes in normal human prostate tissues. Clin. Cancer Res.13,3796–3802 (2007).
Medline CASGoogle Scholar
145 Wolff EM, Liang G, Cortez CC et al.: RUNX3 methylation reveals that bladder tumors are older in patients with a history of smoking. Cancer Res.68,6208–6214 (2008).
Medline CASGoogle Scholar

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Published online 17 February 2011

Published in print February 2011

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The contents of this article is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the NIH.

Financial & competing interests disclosure

This publication was supported in part by grant number P30 CA006927 from the National Cancer Institute. Additional funds were provided by Fox Chase Cancer Center via institutional support of the Kidney Cancer Keystone Program. Paul Cairns has received financial compensation as a member of the scientific advisory board for Oncomethylome Sciences Inc. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

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Epigenetics of kidney cancer and bladder cancer

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