Somatic VHL alteration and its impact on prognosis in patients with clear cell renal cell carcinoma

Abstract

4602 Backgrounds: Somatic inactivation of the von Hippel-Lindau (VHL) gene is the most frequent genetic event observed in clear cell renal cell carcinomas (CC-RCCs). However, the prognostic relevance of somatic VHL alteration and its target, hypoxia inducible factor (HIF)-1α, has not been defined. We investigated the genetic changes in the VHL gene and HIF-1α and studied their clinical implications in patients with sporadic CC-RCC. Methods: Patients who underwent nephrectomy were eligible if they had pathologically confirmed CC-RCC that was 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 (PCR-SSCP) analysis was performed to detect VHL mutations and genetic changes in HIF-1α, which were followed by automated direct sequencing. VHL hypermethylation was examined by methylation-specific PCR. Results: A total of 56 patients were enrolled and somatic VHL alterations were detected in 16 (29%); intragenic mutation in eight, hypermethylation in five, and both alteration 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 a ‘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), The CC-RCCs with missense mutation seem to have had better responses to immunotherapy. The Pro582Ser change in HIF-1α was detected in six patients (11%) and was positively correlated with the development of metastases (P=0.023). Concluions: 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-1α may contribute to the development of metastases. No significant financial relationships to disclose.