Tumor necrosis factor-alpha gene mutations and genotype changes in renal cell carcinoma

Purpose: We tested the hypothesis that genotype changes in the promoter reg ion of tumor necrosis factor-alpha and exon 1 are associated with renal cel l carcinoma. Materials and Methods: We analyzed genotypic changes at the 3 polymorphic l oci of tumor necrosis factor-alpha -238, -308 and 488 using tumor and norma l tissues from 81 Japanese patients with renal cell carcinoma. Results: Of the 81 patients 14 (17%) had point mutations from G to A, inclu ding 8 (57%) with point mutations at multiple loci. Six of the 8 patients ( 75%) with point mutations at multiple loci were classified with stage 4 ren al cell carcinoma. Of the 81 patients 14 were classified with stage 4 carci noma, including 9 (64%) with point mutation from G to A. Normal tissue from cancer patients showed an increased frequency of the GA genotype at loci - 238 and 488 compared to healthy controls (37% versus 9% and 30% versus 12%, respectively). The relative risk of renal cell carcinoma was 6.5-fold high er in patients with the GA genotype at locus -238 (p <0.001) and 2.9-fold h igher in those with the GA genotype at locus 488 (0.01 < p <0.025) when com paring normal tissue from renal cell carcinoma patients with that of health y controls. Conclusions: Point mutation from G to A, and the GA genotype at loci -238 a nd 488 of the TNF-<alpha> gene were common in patients with advanced renal cell carcinoma. The genotype change at loci -238 and 488 of the TNF-alpha g ene are associated with renal cancer pathogenesis.