VHL Alterations in Human Clear Cell Renal Cell Carcinoma: Association with Advanced Tumor Stage and a Novel Hot Spot Mutation
2000
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 pT 1 , pT 2 , and
pT 3 CCRCCs and the VHL
mutation/hypermethylation detection rate varied among these three
groups. Altogether, VHL alterations were significantly
associated with pT 3 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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