title: Mutational status of VHL gene and its clinical importance in renal clear cell carcinoma.
abstract: The most common subtype of renal cell carcinoma is the clear cell type (ccRCC), accounting for 75 % of cases. Inactivation of VHL gene is thought to be an early event in ccRCC carcinogenesis. Our intention was to assess whether VHL mutational status might provide useful predictive or prognostic information in patients with ccRCC. VHL messenger RNA (mRNA) expression was analyzed by in situ hybridization and its protein by immunohistochemistry on a tissue microarray containing samples from 148 cases. This was validated by qRT-PCR on 62 cases, for which RNA was available. The mutation status was assessed in 91 cases by Sanger sequencing. VHL was found mutated in 57 % of cases, with missense mutations in 26 %, nonsense in 5 %, splice site in 13 %, deletions in 39 %, indels in 8 %, duplications in 8 %, and insertions in 2 % of the cases. The prevalence of mutations by exon was the following: exon 1, 47 %; exon 2, 27 %; and exon 3, 13 %. VHL protein was expressed in a high number of cases (80 %), but significant correlations were not found between protein expression, clinical data, and survival. Importantly, of the 91 samples evaluated by sequencing, 45 were mutated, and 87 % of those were strongly positive. We found 32 novel mutations in the VHL gene in ccRCC. The presence of mutations was not concordant with mRNA or protein expression. Nonsense mutations of the VHL gene appear to be related with poorer prognosis and survival.
authors.affiliation: International Center of Research in Cancer (CIPE), A.C. Camargo Cancer Center, Rua Taguá, 440-Liberdade, 01508-010, Sao Paulo, SP, Brazil, mariana.rezendealves@gmail.com.
authors.forename: Mariana Rezende
authors.initials: MR
authors.lastname: Alves
authors.forename: Felipe Cavalcanti
authors.initials: FC
authors.lastname: Carneiro
authors.forename: André Mourão
authors.initials: AM
authors.lastname: Lavorato-Rocha
authors.forename: Walter Henriques
authors.initials: WH
authors.lastname: da Costa
authors.forename: Isabela Werneck
authors.initials: IW
authors.lastname: da Cunha
authors.forename: Stênio
authors.initials: S
authors.lastname: de Cássio Zequi
authors.forename: Gustavo Cardoso
authors.initials: GC
authors.lastname: Guimaraes
authors.forename: Fernando Augusto
authors.initials: FA
authors.lastname: Soares
authors.forename: Dirce Maria
authors.initials: DM
authors.lastname: Carraro
authors.forename: Rafael Malagoli
authors.initials: RM
authors.lastname: Rocha
mesh_terms: D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D005260:Female; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D012333:RNA, Messenger / Q000032:analysis; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000032:analysis / Q000235:genetics*
chemical_list: D012333:RNA, Messenger; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human