title: CA9 gene: single nucleotide polymorphism predicts metastatic renal cell carcinoma prognosis.
abstract: OBJECTIVE
  We assessed CA9 single nucleotide polymorphisms and mutations, and their association with CAIX protein expression, overall survival and response to interleukin-2 in white patients with metastatic clear cell renal cell carcinoma.
  
  
  METHODS
  Genomic DNA was extracted from frozen tumor samples of 54 metastatic clear cell renal cell carcinomas. The CA9 gene exons and flanking regions were amplified by polymerase chain reaction and sequenced. The monoclonal antibody M75 was used to evaluate CAIX protein expression in the primary tumor by immunohistochemistry.
  
  
  RESULTS
  CA9 reference single nucleotide polymorphisms rs2071676, rs12553173, rs3829078 and rs1048638 were found in 59%, 15%, 11% and 33% of patients, respectively. The deletion c.376del393 was observed in 2 patients. CAIX expression was greater than 85% in 65% of patients. No single nucleotide polymorphisms were significantly associated with CAIX expression. Patients with the C allele variant of rs12553173 had improved median survival (27.3 vs 13.6 months, p = 0.0431) and a greater likelihood of an interleukin-2 response (57% vs 22%, p = 0.081) Likewise high CAIX expression was associated with longer median survival (25.5 vs 8.5 months, p <0.0001) and a greater interleukin-2 response rate (37% vs 8%, p = 0.070). In a multivariate Cox model the C allele variant of CA9 single nucleotide polymorphism rs12553173 and CAIX expression were retained as independent prognostic factors.
  
  
  CONCLUSIONS
  CA9 single nucleotide polymorphisms are common in patients with metastatic clear cell renal cell carcinoma. The synonymous C allele variant of rs12553173 may be associated with improved overall survival and a greater likelihood of a response to interleukin-2. CA9 rs12553173 and CAIX are independent prognostic factors of overall survival and complementary for predicting the prognosis of metastatic clear cell renal cell carcinoma.
authors.affiliation: Department of Urology, University of California-Los Angeles, Los Angeles, California 90095-1738, USA.
authors.forename: Michela
authors.initials: M
authors.lastname: de Martino
authors.forename: Tobias
authors.initials: T
authors.lastname: Klatte
authors.forename: David B
authors.initials: DB
authors.lastname: Seligson
authors.forename: Jeffrey
authors.initials: J
authors.lastname: LaRochelle
authors.forename: Brian
authors.initials: B
authors.lastname: Shuch
authors.forename: Randy
authors.initials: R
authors.lastname: Caliliw
authors.forename: Zhenhua
authors.initials: Z
authors.lastname: Li
authors.forename: Fairooz F
authors.initials: FF
authors.lastname: Kabbinavar
authors.forename: Allan J
authors.initials: AJ
authors.lastname: Pantuck
authors.forename: Arie S
authors.initials: AS
authors.lastname: Belldegrun
mesh_terms: D000328:Adult; D000368:Aged; D000951:Antigens, Neoplasm / Q000235:genetics*; D000970:Antineoplastic Agents / Q000627:therapeutic use; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases / Q000235:genetics*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000556:secondary*; D005260:Female; D006801:Humans; D007376:Interleukin-2 / Q000627:therapeutic use; D007680:Kidney Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D015996:Survival Rate
chemical_list: D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D007376:Interleukin-2; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases