title: Patterns of gene expression and copy-number alterations in von-hippel lindau disease-associated and sporadic clear cell carcinoma of the kidney.
abstract: Recent insights into the role of the von-Hippel Lindau (VHL) tumor suppressor gene in hereditary and sporadic clear-cell renal cell carcinoma (ccRCC) have led to new treatments for patients with metastatic ccRCC, although virtually all patients eventually succumb to the disease. We performed an integrated, genome-wide analysis of copy-number changes and gene expression profiles in 90 tumors, including both sporadic and VHL disease-associated tumors, in hopes of identifying new therapeutic targets in ccRCC. We identified 14 regions of nonrandom copy-number change, including 7 regions of amplification (1q, 2q, 5q, 7q, 8q, 12p, and 20q) and 7 regions of deletion (1p, 3p, 4q, 6q, 8p, 9p, and 14q). An analysis aimed at identifying the relevant genes revealed VHL as one of three genes in the 3p deletion peak, CDKN2A and CDKN2B as the only genes in the 9p deletion peak, and MYC as the only gene in the 8q amplification peak. An integrated analysis to identify genes in amplification peaks that are consistently overexpressed among amplified samples confirmed MYC as a potential target of 8q amplification and identified candidate oncogenes in the other regions. A comparison of genomic profiles revealed that VHL disease-associated tumors are similar to a subgroup of sporadic tumors and thus more homogeneous overall. Sporadic tumors without evidence of biallelic VHL inactivation fell into two groups: one group with genomic profiles highly dissimilar to the majority of ccRCC and a second group with genomic profiles that are much more similar to tumors with biallelic inactivation of VHL.
authors.affiliation: Departments of Medical Oncology, Harvard Medical School, Boston, Massachusetts, USA. rameen@broad.mit.edu
authors.forename: Rameen
authors.initials: R
authors.lastname: Beroukhim
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Brunet
authors.forename: Arianna
authors.initials: A
authors.lastname: Di Napoli
authors.forename: Kirsten D
authors.initials: KD
authors.lastname: Mertz
authors.forename: Apryle
authors.initials: A
authors.lastname: Seeley
authors.forename: Maira M
authors.initials: MM
authors.lastname: Pires
authors.forename: David
authors.initials: D
authors.lastname: Linhart
authors.forename: Robert A
authors.initials: RA
authors.lastname: Worrell
authors.forename: Holger
authors.initials: H
authors.lastname: Moch
authors.forename: Mark A
authors.initials: MA
authors.lastname: Rubin
authors.forename: William R
authors.initials: WR
authors.lastname: Sellers
authors.forename: Matthew
authors.initials: M
authors.lastname: Meyerson
authors.forename: W Marston
authors.initials: WM
authors.lastname: Linehan
authors.forename: William G
authors.initials: WG
authors.lastname: Kaelin
authors.forename: Sabina
authors.initials: S
authors.lastname: Signoretti
mesh_terms: D002292:Carcinoma, Renal Cell / Q000150:complications / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D055028:Comparative Genomic Hybridization; D018628:Gene Dosage; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D005787:Gene Frequency; D055106:Genome-Wide Association Study; D006801:Humans; D007668:Kidney / Q000473:pathology; D007680:Kidney Neoplasms / Q000150:complications / Q000235:genetics* / Q000473:pathology; D009362:Neoplasm Metastasis; D020641:Polymorphism, Single Nucleotide; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics; D006623:von Hippel-Lindau Disease / Q000150:complications / Q000235:genetics* / Q000473:pathology
chemical_list: D051794:Von Hippel-Lindau Tumor Suppressor Protein