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VHL Alterations in Human Clear Cell Renal Cell Carcinoma: Association with Advanced Tumor Stage and a Novel Hot Spot Mutation¹

Hiltrud Brauch², Gregor Weirich, Jürgen Brieger, Damjan Glava, Heinz Rödl, Mariola Eichinger, Matthias Feurer, Eberhardt Weidt, Chutintorn Puranakanitstha, Christine Neuhaus, Sigmund Pomer, Walburgis Brenner, Peter Schirmacher, Stephan Störkel, Michael Rotter, Andrej Maera, Nadja Gugeler and Hans-Joachim Decker

Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, 70376 Stuttgart, Germany [H. B., N. G.]; Laboratory of Molecular Pathology, Institute of Pathology, TUM, 81675 Munich, Germany [G. W., H. R., M. E., M. F., M. R.]; Laboratory of Immunobiology, National Cancer Institute-Frederick Cancer Research and Development Center, Frederick, Maryland 21702 [G. W.]; Hematology, Third Department of Medicine, University of Mainz, 55131 Mainz, Germany [J. B., E. W., C. P., C. N., H-J. D.]; Laboratory of Molecular Genetics, Institute of Pathology, University of Ljubljana, 1000 Ljubljana, Slovenia [D. G., A. M.]; Department of Urology, University of Heidelberg, 69120 Heidelberg, Germany [S. P.]; Department of Urology [W. B.] and Institute of Pathology [P. S.], University of Mainz, 55131 Mainz, Germany; Institute of Pathology, University of Witten-Herdecke, 42283 Wuppertal, Germany [S. S.]; and Department of Molecular Genetics, Bioscientia Institute, 55218 Ingelheim, Germany [H-J. D.]

To elucidate the role of somatic alterations for renal cancer etiology and prognosis, we analyzed 227 sporadic renal epithelial tumors for mutations and hypermethylations in the von Hippel-Lindau tumor suppressor gene VHL. Tumors were classified according to the recommendations of the Union Internationale Contre le Cancer (UICC) and the American Joint Committee on Cancer (AJCC). Somatic VHL mutations were identified by PCR, single-strand conformation polymorphism analysis, and sequencing, and hypermethylations were identified by restriction enzyme digestion and Southern blotting. Frequencies of VHL alterations were established, and an association with tumor type or tumor type and tumor stage was evaluated. VHL mutations and hypermethylations were identified in 45% of clear cell renal cell carcinomas (CCRCCs) and occasionally (3 of 28) in papillary (chromophilic) renal cell carcinomas (RCCs). Lack of VHL mutations and hypermethylations in chromophobe RCCs and oncocytomas was statistically significant (P = 0.0001 and P = 0.0004, respectively). RCCs carrying VHL alterations showed, in nine cases (12%), mutations at a hot spot involving a thymine repeat (ATT.TTT) in exon 2. Tumor staging was critical to the VHL mutation/hypermethylation detection rate in CCRCCs shown by separate evaluation of patients from medical centers in Munich, Heidelberg, and Mainz. The spectrum of pT₁, pT₂, and pT₃ CCRCCs and the VHL mutation/hypermethylation detection rate varied among these three groups. Altogether, VHL alterations were significantly associated with pT₃ CCRCCs (P = 0.009). This is the first evidence of frequent somatic VHL mutations at a particular site within exon 2 and an association of VHL mutations/hypermethylations with a standard prognostic factor.

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