Low CAIX expression and absence of VHL gene mutation are associated with tumor aggressiveness and poor survival of clear cell renal cell carcinoma.
We attempted to describe, in a series of clear cell renal cell carcinoma (RCC), the relationship between CAIX expression, VHL gene mutations, tumor characteristics and outcome. Radical nephrectomy was performed in 100 patients. Genomic DNA was extracted from frozen tumor samples. Four amplimers covering the whole coding sequence of the VHL gene were synthesized by PCR and sequenced. The monoclonal antibody M75 was used to evaluate CAIX protein expression immunohistochemically. VHL mutations were identified in 58 patients (58%) and high CAIX expression (>85%) was observed in 78 (78%). Tumors with VHL mutation showed higher CAIX expression than those without (p = 0.02). Low CAIX expression and absence of VHL mutation were associated with a more advanced tumors e.g., higher T stages and presence of metastases. VHL mutation and high CAIX expression predicted longer progression-free survival (p = 0.037) and disease-specific survival (p = 0.001), respectively. In combination, they defined three prognostic groups (p = 0.002): (i) good prognosis, defined as VHL mutation and high CAIX (2-year survival: 86%), (ii) intermediate prognosis with either VHL mutation or high CAIX (69%), and (iii) poor prognosis with no VHL mutation and low CAIX (45%, median survival 18 months). CAIX expression, but not VHL mutational status, was an independent prognostic factor in multivariate analysis. Taken together, CAIX expression and VHL mutational status are able to stratify patients with clear cell RCC into distinct groups with regards to clinicopathological variables and prognosis, with low CAIX expression and absence of VHL mutation being associated with a poor clinicopathological phenotype and diminished survival.
Patard
Jean-Jacques
JJ
CNRS UMR6061 Genetics and development, IFR 140, University of Rennes 1, Rennes, France.
Fergelot
Patricia
P
CNRS UMR6061 Genetics and development, IFR 140, University of Rennes 1, Rennes, France.
Karakiewicz
Pierre I
PI
Cancer Prognostics and Health Outcome Unit, University of Montreal Health Center, Montreal, Quebec, Canada.
Klatte
Tobias
T
Department of Urology, University of California, Los Angeles, CA.
Trinh
Quoc-Dien
QD
Cancer Prognostics and Health Outcome Unit, University of Montreal Health Center, Montreal, Quebec, Canada.
Rioux-Leclercq
Nathalie
N
CNRS UMR6061 Genetics and development, IFR 140, University of Rennes 1, Rennes, France.
Said
Jonathan W
JW
Department of Urology, University of California, Los Angeles, CA.|Department of Pathology and Laboratory Medicine, University of California, Los Angeles, CA.
Belldegrun
Arie S
AS
Department of Urology, University of California, Los Angeles, CA.
Pantuck
Allan J
AJ
Department of Urology, University of California, Los Angeles, CA.
D000368:Aged; D000951:Antigens, Neoplasm / Q000378:metabolism*; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases / Q000378:metabolism*; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D015536:Down-Regulation; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009154:Mutation; D009367:Neoplasm Staging; D016016:Proportional Hazards Models; D016019:Survival Analysis; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics*
D000951:Antigens, Neoplasm; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases; C497446:VHL protein, human