Author/Editor		Brauch, H; Weirich, G; Brieger, J; Glavač, D; Rodl, H; Eichinger, M; Feurer, M; Weidt, E; Puranakanitstha, C; Neuhaus, C; Mašera, A
Title		VHL alterations in human clear cell renal cell carcinoma: association with advanced tumor stage and a novel hot spot mutation
Type		članek
Source		Cancer Res
Vol. and No.		Letnik 60, št. 7
Publication year		2000
Volume		str. 1942-8
Language		eng
Abstract		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 nternationale 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.
Descriptors		CARCINOMA, RENAL CELL GENES, SUPPRESSOR, TUMOR KIDNEY NEOPLASMS MUTATION PROTEINS ADENOMA, OXYPHILIC AMINO ACIDS DNA METHYLATION DNA, NEOPLASM FRAMESHIFT MUTATION GENE EXPRESSION REGULATION, NEOPLASTIC NEOPLASM STAGING POINT MUTATION POLYMORPHISM, SINGLE-STRANDED CONFORMATIONAL SEQUENCE DELETION