Localization of point mutations in the coding part of the VHL gene in clear cell renal cancer

Abstract

The VHL gene is often inactivated in sporadic clear cell renal cancer (CCRC) due to somatic mutations, and its germline mutations cause hereditary CCRC: von Hippel-Lindau syndrome. Localization of mutations in VHL, identification of new mutations, and their influence on CCRC progression and sensi tivity to targeted therapy are topical problems in modern oncogenetics. In the current work, we identified and characterized mutations in 248 primary CCRCs using SSCP analysis and sequencing. Somatic mutations were detected in 37.5% of samples, with 72% of mutations identified for the first time. New missense muta tions were analyzed by alignment programs and three dimensional structure modeling. Mutation frequency was compared in different groups of patients with respect to stage, grade, and metastases. It was demonstrated that 39.1% of samples of stage I harbored somatic mutations; however, no association with progression or metastases was found. We also investigated localization of mutations in the VHL coding part and positions of missense mutations and inframe deletions/insertions, focusing on VHL critical sequences. The VHL muta tion analysis performed in this study expands the opportunities of laboratory diagnostics of familial and spo radic CCRC.