title: Integrative genomic analyses of sporadic clear cell renal cell carcinoma define disease subtypes and potential new therapeutic targets.
abstract: Sporadic clear cell renal cell carcinoma (ccRCC), the most common type of adult kidney cancer, is often associated with genomic copy number aberrations on chromosomes 3p and 5q. Aberrations on chromosome 3p are associated with inactivation of the tumor suppressor gene von-Hippel Lindau (VHL), which activates the hypoxia-inducible factors HIF1α and HIF2α. In contrast, ccRCC genes on chromosome 5q remain to be defined. In this study, we conducted an integrated analysis of high-density copy number and gene expression data for 54 sporadic ccRCC tumors that identified the secreted glycoprotein STC2 (stanniocalcin 2) and the proteoglycan VCAN (versican) as potential 5q oncogenes in ccRCCs. In functional assays, STC2 and VCAN each promoted tumorigenesis by inhibiting cell death. Using the same approach, we also investigated the two VHL-deficient subtypes of ccRCC, which express both HIF1α and HIF2α (H1H2) or only HIF2α (H2). This analysis revealed a distinct pattern of genomic aberrations in each group, with the H1H2 group displaying, on average, a more aberrant genome than the H2 group. Together our findings provide a significant advance in understanding ccRCCs by offering a molecular definition of two subtypes with distinct characteristics as well as two potential chromosome 5q oncogenes, the overexpression of which is sufficient to promote tumorigenesis by limiting cell death.
authors.affiliation: Department of Medicine, Abramson Family Cancer Research Institute, Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Vijay R
authors.initials: VR
authors.lastname: Dondeti
authors.forename: Bradley
authors.initials: B
authors.lastname: Wubbenhorst
authors.forename: Priti
authors.initials: P
authors.lastname: Lal
authors.forename: John D
authors.initials: JD
authors.lastname: Gordan
authors.forename: Kurt
authors.initials: K
authors.lastname: D'Andrea
authors.forename: Edward F
authors.initials: EF
authors.lastname: Attiyeh
authors.forename: M Celeste
authors.initials: MC
authors.lastname: Simon
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Nathanson
mesh_terms: D002292:Carcinoma, Renal Cell / Q000145:classification / Q000235:genetics* / Q000628:therapy; D045744:Cell Line, Tumor; D018628:Gene Dosage; D020869:Gene Expression Profiling; D023281:Genomics; D006801:Humans; D007680:Kidney Neoplasms / Q000145:classification / Q000235:genetics* / Q000628:therapy
references.citation: PLoS Biol. 2003 Dec;1(3):E83
references.pmid: 14691554
references.citation: Clin Cancer Res. 2008 Aug 1;14(15):4726-34
references.pmid: 18676741
references.citation: Nat Genet. 2006 May;38(5):500-1
references.pmid: 16642009
references.citation: Clin Cancer Res. 2009 Dec 15;15(24):7582-7592
references.pmid: 19996202
references.citation: Mutat Res. 2008 Dec 1;647(1-2):21-9
references.pmid: 18723033
references.citation: Gynecol Oncol. 2010 Oct;119(1):114-20
references.pmid: 20619446
references.citation: Nature. 2010 Feb 18;463(7283):899-905
references.pmid: 20164920
references.citation: Cancer Sci. 2009 May;100(5):914-9
references.pmid: 19298603
references.citation: J Pathol. 2010 Jun;221(2):125-38
references.pmid: 20225241
references.citation: Int J Cancer. 2009 Aug 15;125(4):926-31
references.pmid: 19415750
references.citation: Int J Cancer. 2008 Oct 1;123(7):1545-50
references.pmid: 18623083
references.citation: Cancer Cell. 2010 May 18;17(5):443-54
references.pmid: 20478527
references.citation: Cancer Res. 2009 Jun 1;69(11):4674-81
references.pmid: 19470766
references.citation: Nature. 2010 Jan 21;463(7279):360-3
references.pmid: 20054297
references.citation: Lancet. 2009 Mar 28;373(9669):1119-32
references.pmid: 19269025
references.citation: BMC Cancer. 2010 Oct 04;10:524
references.pmid: 20920340
references.citation: Cancer Cell. 2008 Dec 9;14(6):435-46
references.pmid: 19061835
references.citation: BJU Int. 2009 Jan;103(2):165-70
references.pmid: 18782313
references.citation: Curr Opin Genet Dev. 2007 Feb;17(1):71-7
references.pmid: 17208433
references.citation: Curr Oncol Rep. 2010 May;12(3):193-201
references.pmid: 20425079
references.citation: Mol Biol Cell. 2005 Mar;16(3):1330-40
references.pmid: 15635104
references.citation: Genes Dev. 2007 Mar 1;21(5):525-30
references.pmid: 17344414
references.citation: Genes Dev. 2010 Feb 15;24(4):327-32
references.pmid: 20123895
references.citation: Cancer Lett. 2008 Jun 28;265(1):76-83
references.pmid: 18355956
references.citation: Nat Cell Biol. 2010 Nov;12(11):1108-14
references.pmid: 20935635
references.citation: Curr Opin Cell Biol. 2002 Oct;14(5):617-23
references.pmid: 12231358
references.citation: Eur Urol. 2009 Mar;55(3):669-78
references.pmid: 18450365
references.citation: Arch Pathol Lab Med. 2009 Dec;133(12):1917-22
references.pmid: 19961245
references.citation: Cancer Cell. 2011 Jan 18;19(1):86-100
references.pmid: 21215703
references.citation: Mol Cell Biol. 2005 Jul;25(13):5675-86
references.pmid: 15964822
references.citation: J Clin Oncol. 2009 Feb 10;27(5):746-53
references.pmid: 19124809
references.citation: Genes Chromosomes Cancer. 2010 Jul;49(7):610-9
references.pmid: 20461753
references.citation: Nature. 2011 Jan 27;469(7331):539-42
references.pmid: 21248752
references.citation: Cancer Cell. 2007 Apr;11(4):335-47
references.pmid: 17418410