title: DNA methylation status defines clinicopathological parameters including survival for patients with clear cell renal cell carcinoma (ccRCC).
abstract: Epigenetic alterations in the methylome have been associated with tumor development and progression in renal cell carcinoma (RCC). In this study, 45 tumor samples, 12 tumor-free kidney cortex tissues, and 24 peripheral blood samples from patients with clear cell RCC (ccRCC) were analyzed by genome-wide promoter-directed methylation arrays and related to clinicopathological parameters. Unsupervised hierarchical clustering separated the tumors into two distinct methylation groups (clusters A and B), where cluster B had higher average methylation and increased number of hypermethylated CpG sites (CpGs). Furthermore, tumors in cluster B had, compared with cluster A, a larger tumor diameter (p = 0.033), a higher morphologic grade (p < 0.001), a higher tumor-node-metastasis (TNM) stage (p < 0.001), and a worse prognosis (p = 0.005). Higher TNM stage was correlated to an increase in average methylation level (p = 0.003) and number of hypermethylated CpGs (p = 0.003), whereas a number of hypomethylated CpGs were mainly unchanged. However, the predicted age of the tumors based on methylation profile did not correlate with TNM stage, morphological grade, or methylation cluster. Differently methylated (DM) genes (n = 840) in ccRCC samples compared with tumor-free kidney cortex samples were predominantly hypermethylated and a high proportion were identified as polycomb target genes. The DM genes were overrepresented by transcription factors, ligands, and receptors, indicating functional alterations of significance for ccRCC progression. To conclude, increased number of hypermethylated genes was associated with increased TNM stage of the tumors. DNA methylation classification of ccRCC tumor samples at diagnosis can serve as a clinically applicable prognostic marker in ccRCC.
authors.affiliation: Department of Medical Biosciences, Pathology, Umeå University, SE-90185, Umeå, Sweden.
authors.forename: Emma Andersson
authors.initials: EA
authors.lastname: Evelönn
authors.affiliation: Department of Medical Biosciences, Pathology, Umeå University, SE-90185, Umeå, Sweden.
authors.forename: Sofie
authors.initials: S
authors.lastname: Degerman
authors.affiliation: Department of Medical Biosciences, Pathology, Umeå University, SE-90185, Umeå, Sweden.
authors.forename: Linda
authors.initials: L
authors.lastname: Köhn
authors.affiliation: Department of Medical Biosciences, Pathology, Umeå University, SE-90185, Umeå, Sweden.|Department of Mathematics and Mathematical Statistics, Umeå University, Umeå, Sweden.
authors.forename: Mattias
authors.initials: M
authors.lastname: Landfors
authors.affiliation: Department of Surgical and Perioperative Sciences, Urology and Andrology, Umeå University, Umeå, Sweden.
authors.forename: Börje
authors.initials: B
authors.lastname: Ljungberg
authors.affiliation: Department of Medical Biosciences, Pathology, Umeå University, SE-90185, Umeå, Sweden. goran.roos@umu.se.
authors.forename: Göran
authors.initials: G
authors.lastname: Roos
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D016000:Cluster Analysis; D019175:DNA Methylation / Q000235:genetics*; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D007680:Kidney Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D016133:Polymerase Chain Reaction; D011379:Prognosis; D016016:Proportional Hazards Models
keywords: Clear cell renal cell carcinoma; DNA methylation; Polycomb target genes; Predicted age; Survival
references.citation: PLoS One. 2014 Jan 15;9(1):e85621
references.pmid: 24454902
references.citation: Can J Urol. 2008 Apr;15(2):3954-66
references.pmid: 18405442
references.citation: Scand J Urol. 2014 Jun;48(3):231-8
references.pmid: 24666102
references.citation: Cancer Res. 2006 Feb 15;66(4):2000-11
references.pmid: 16488999
references.citation: Epigenetics. 2012 Mar;7(3):278-90
references.pmid: 22430804
references.citation: Oncogene. 2010 Apr 8;29(14):2104-17
references.pmid: 20154727
references.citation: Mol Cell. 2013 Jan 24;49(2):359-367
references.pmid: 23177740
references.citation: Nature. 2011 Jan 20;469(7330):343-9
references.pmid: 21248841
references.citation: Oncogene. 2011 Mar 24;30(12):1390-401
references.pmid: 21132003
references.citation: Int Urol Nephrol. 2014 Mar;46(3):539-53
references.pmid: 23943374
references.citation: Clin Cancer Res. 2004 Jun 15;10(12 Pt 1):3972-9
references.pmid: 15217927
references.citation: Genome Biol. 2013;14(10):R115
references.pmid: 24138928
references.citation: Neoplasia. 2014 Jul;16(7):606-15
references.pmid: 25065939
references.citation: Cancer Res. 2001 Oct 1;61(19):7277-81
references.pmid: 11585766
references.citation: Am J Surg Pathol. 1982 Oct;6(7):655-63
references.pmid: 7180965
references.citation: Nucleic Acids Res. 2005 Dec 02;33(21):6823-36
references.pmid: 16326863
references.citation: Int J Cancer. 2008 Oct 1;123(7):1545-50
references.pmid: 18623083
references.citation: N Engl J Med. 2008 Mar 13;358(11):1148-59
references.pmid: 18337604
references.citation: Expert Opin Med Diagn. 2011 Jan;5(1):37-47
references.pmid: 23484475
references.citation: Genome Med. 2010 Sep 03;2(9):59
references.pmid: 20815920
references.citation: ISRN Gastroenterol. 2014 Mar 06;2014:464015
references.pmid: 24729878
references.citation: Carcinogenesis. 2012 Aug;33(8):1487-93
references.pmid: 22610075
references.citation: Cell. 2006 Apr 21;125(2):301-13
references.pmid: 16630818
references.citation: Appl Immunohistochem Mol Morphol. 2015 May-Jun;23 (5):334-42
references.pmid: 24992170
references.citation: Proc Natl Acad Sci U S A. 1994 Oct 11;91(21):9700-4
references.pmid: 7937876
references.citation: Genome Biol. 2015 May 13;16:96
references.pmid: 25968125
references.citation: PLoS One. 2013 Nov 27;8(11):e81484
references.pmid: 24312307
references.citation: BJU Int. 2011 Jul;108(2 Pt 2):E29-35
references.pmid: 21435154
references.citation: Bioessays. 2015 Jan;37(1):20-4
references.pmid: 25303747
references.citation: Cancer Res. 2009 Apr 1;69(7):2896-901
references.pmid: 19318563
references.citation: Cancer Treat Rev. 2008 May;34(3):193-205
references.pmid: 18313224
references.citation: PLoS One. 2014 Feb 21;9(2):e89376
references.pmid: 24586730
references.citation: Oncogene. 2007 Aug 16;26(38):5680-91
references.pmid: 17353908
references.citation: PLoS One. 2013 Jun 06;8(6):e65373
references.pmid: 23762353
references.citation: Mol Cell. 2008 Nov 21;32(4):503-18
references.pmid: 19026781
references.citation: Int J Cancer. 2006 Jul 15;119(2):288-96
references.pmid: 16453286
references.citation: Tumour Biol. 2015 Sep;36(9):7159-66
references.pmid: 25877750