JAK3 in clear cell renal cell carcinoma: mutational screening and clinical implications.

OBJECTIVES: 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.

PATIENTS AND 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.