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402 MUTATIONS IN THE VON HIPPEL-LANDAU TUMOR SUPPRESSOR PROTEIN CONFER RESISTANCE TO IONIZING RADIATION.
  1. A. M. Kloepfer1,
  2. B. A. Frederick1,
  3. D. Raben1
  1. 1Department of Radiation Oncology, University of Colorado at Denver and Health Sciences Center School of Medicine, Denver, CO

Abstract

Purpose Renal cell carcinoma (RCC) has historically been regarded as a radiation-resistant malignancy, and radiotherapy has no current role in the management of primary tumors. The von Hippel-Landau (VHL) tumor suppressor gene has been shown to have a role in UV-radiation protection and is frequently mutated in a high percentage of RCCs. This study investigated the radiation sensitivity of RCC cell lines with point mutations in the VHL gene associated with disease to determine if VHL mutational status is associated with radiation resistance.

Methods The renal cell line 786-0 was stably transfected with wild-type VHL, or V84L, Y98H, F119S, L188Q, or L188V VHL mutations. Radiation sensitivity was determined by irradiating cells in 96-well plates at 0, 2, 4, 6, or 8 Gy, followed by a 5-day incubation and assaying viability with thiazolyl blue tetrazolium bromide reduction. VHL protein expression was determined by immunoblotting after radiation treatment.

Results Radiation had similar effects on all cell lines regardless of VHL status, except for L188V, which was significantly more radiation resistant than the other cell lines. VHL protein expression was down-regulated in a dose-dependent manner with radiation only in the L188V mutant line.

Conclusions Preliminary data suggest that the response of RCC cell lines to radiation may depend on the specific VHL mutation. Studies are currently in progress to determine if radiation induces microRNAs that may be associated with differences in VHL expression.

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