title: JAK3 in clear cell renal cell carcinoma: mutational screening and clinical implications.
abstract: OBJECTIVE
  Janus Kinase 3 (JAK3) mediates cytokine signaling and T-cell activation. We hypothesized that JAK3 mutations may contribute to the development and progression of clear cell renal cell carcinoma (ccRCC). To test this hypothesis, we performed mutational screening and functional studies.
  
  
  METHODS
  This hospital-based case-control study included 50 patients with ccRCC and 100 age- and gender-matched controls. Both genomic and tumor DNA were extracted. All 23 JAK3 exons were amplified by PCR and analyzed by denaturing high-performance liquid chromatography and automatic sequencing. Effects of JAK3 mutations on interleukin-2-stimulated peripheral T-cells were analyzed by confocal laser-scanning microscopy and immunoprecipitation.
  
  
  RESULTS
  Four different JAK3 germline missense mutations (p.Gln13Lys; p.Arg925Ser; p.Ala677Thr, p.Val722Ile) were found in a total of 7 ccRCC patients (14%), but in none of the controls (P = 0.0006). All germline mutations were similarly detected in the tumors. An additional somatic missense mutation (p.Tyr238Cys) was found in a patient who had a germline mutation. Four of the mutations have not been previously described (p.Gln13Lys; p.Arg925Ser; p.Ala677Thr, p.Tyr238Cys). Patients with JAK3 mutations more frequently presented with metastases (3 out of 4 [75%] vs. 4 out of 46 [9%]; P = 0.004) and had poorer survival (P = 0.049). In p.Arg925Ser and p.Ala677Thr/p.Val722Ile, functional analyses showed abnormal JAK3 and STAT5 tyrosine phosphorylation and a reduction of JAK3/STAT5 interaction.
  
  
  CONCLUSIONS
  JAK3 mutations are found in a subset of ccRCC patients and may be associated with ccRCC development and a greater risk of metastases. JAK3 function is compromised in p.Arg925Ser and p.Ala677Thr/p.Val722Ile. Future studies with a larger number of patients need to confirm these findings.
authors.affiliation: Department of Urology and Renal Transplantation, University of Foggia, Foggia, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: de Martino
authors.forename: Maddalena
authors.initials: M
authors.lastname: Gigante
authors.forename: Luigi
authors.initials: L
authors.lastname: Cormio
authors.forename: Clelia
authors.initials: C
authors.lastname: Prattichizzo
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Cavalcanti
authors.forename: Margherita
authors.initials: M
authors.lastname: Gigante
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Ariano
authors.forename: Giuseppe S
authors.initials: GS
authors.lastname: Netti
authors.forename: Eustacchio
authors.initials: E
authors.lastname: Montemurno
authors.forename: Vito
authors.initials: V
authors.lastname: Mancini
authors.forename: Michele
authors.initials: M
authors.lastname: Battaglia
authors.forename: Loreto
authors.initials: L
authors.lastname: Gesualdo
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Carrieri
authors.forename: Elena
authors.initials: E
authors.lastname: Ranieri
mesh_terms: D000368:Aged; D002292:Carcinoma, Renal Cell / Q000235:genetics*; D016022:Case-Control Studies; D004252:DNA Mutational Analysis; D017931:DNA Primers / Q000235:genetics; D018450:Disease Progression; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D018095:Germ-Line Mutation; D006801:Humans; D053616:Janus Kinase 3 / Q000235:genetics*; D007680:Kidney Neoplasms / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D011110:Polymorphism, Genetic; D050799:STAT5 Transcription Factor / Q000235:genetics; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D017931:DNA Primers; D050799:STAT5 Transcription Factor; C507933:JAK3 protein, human; D053616:Janus Kinase 3