title: Somatic VHL alteration and its impact on prognosis in patients with clear cell renal cell carcinoma.
abstract: Somatic inactivation of the von Hippel-Lindau (VHL) gene is the most frequent genetic event observed in clear cell renal cell carcinoma (CC-RCC). However, the prognostic relevance of somatic VHL alteration and its target, hypoxia inducible factor (HIF)-1alpha has not been defined. We investigated the genetic changes in the VHL gene and HIF-1alpha and studied their clinical implications in patients with sporadic CC-RCC. Patients who underwent nephrectomy were eligible if they had pathologically confirmed CC-RCC not associated with VHL disease or familial RCC. Tumor tissues were selected from paraffin blocks on the basis of hematoxylin and eosin (H&E)-stained sections. Polymerase chain reaction-single strand conformation polymorphism analysis was performed to detect VHL mutations and genetic changes in HIF-1alpha, which were followed by automated direct sequencing. VHL hypermethylation was examined by methylation-specific PCR. A total of 56 patients were enrolled and somatic VHL alterations were detected in 16 patients (29%); intragenic mutation in eight, hypermethylation in five, both alterations in three. The mutation types were missense in five patients, silent in three, nonsense in two, and frameshift in one. Somatic VHL alterations were not significantly associated with progression-free survival (PFS) or overall survival (OS). However, patients with 'loss-of-function' VHL mutation showed significantly decreased PFS (P=0.016) and OS (P=0.046). Although the association between VHL alteration and response to immunotherapy was not significant (P=0.486), patients with missense mutation seem to have better response to immunotherapy. The Pro582Ser change in HIF-1alpha was detected in six patients (11%) and was positively correlated with the development of metastases (P=0.023). This study did not show an association between somatic VHL alteration and prognosis in patients with sporadic CC-RCC. However, it suggests that the therapeutic and prognostic implication of somatic VHL alteration may be different according to the mutational subtype and that the Pro582Ser change in HIF-1alpha may contribute to the development of metastases.
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Samsung Medical Center, Ilwon-Dong 50, Gangnam-Gu, Seoul 135-710, Korea.
authors.forename: Jung Han
authors.initials: JH
authors.lastname: Kim
authors.forename: Chul Won
authors.initials: CW
authors.lastname: Jung
authors.forename: Yeon Hee
authors.initials: YH
authors.lastname: Cho
authors.forename: Jeeyun
authors.initials: J
authors.lastname: Lee
authors.forename: Se-Hoon
authors.initials: SH
authors.lastname: Lee
authors.forename: Ho Young
authors.initials: HY
authors.lastname: Kim
authors.forename: Jinny
authors.initials: J
authors.lastname: Park
authors.forename: Joon-Oh
authors.initials: JO
authors.lastname: Park
authors.forename: Kihyun
authors.initials: K
authors.lastname: Kim
authors.forename: Won Seog
authors.initials: WS
authors.lastname: Kim
authors.forename: Young Suk
authors.initials: YS
authors.lastname: Park
authors.forename: Young-Hyuck
authors.initials: YH
authors.lastname: Im
authors.forename: Won Ki
authors.initials: WK
authors.lastname: Kang
authors.forename: Keunchil
authors.initials: K
authors.lastname: Park
mesh_terms: D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000401:mortality / Q000503:physiopathology; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics; D018572:Disease-Free Survival; D016368:Frameshift Mutation; D016147:Genes, Tumor Suppressor; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007680:Kidney Neoplasms / Q000235:genetics* / Q000401:mortality / Q000503:physiopathology; D020125:Mutation, Missense; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D018807:Polymorphism, Single-Stranded Conformational; D016019:Survival Analysis; D014157:Transcription Factors / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D006623:von Hippel-Lindau Disease / Q000235:genetics
chemical_list: D004273:DNA, Neoplasm; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human