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A Single Nucleotide Polymorphism in the Human H-ras Proto-oncogene Determines the Risk of Urinary Bladder Cancer¹

Institute of Clinical Pharmacology, University Medical Center Charité, Humboldt University of Berlin, D-10098 Berlin [A. J., I. R., J. B.], and Department of Clinical Pharmacology, Center of Pharmacology and Toxicology, University Medical Center, Georg-August University, D-37075 Göttingen [J. B.], Germany

Acquired mutations and inherited polymorphisms in the H-ras gene may modulate the risk of urinary bladder cancer. In DNA isolated from bladder cancer tissue, we screened the coding sequence of H-ras, including the exon-intron-junctions, for exon 1 (n = 68 patients), exon 2 (n = 50), and exons 3 and 4 (n = 25). Acquired mutations at codons 12 and 13 (exon 1) and codon 61 (exon 2), which had been described earlier in bladder cancer tissue, were not found in any of the tumors, but we identified a frequent polymorphism at nucleotide 81TC (exon 1) in a wobble position. The clinical impact of this polymorphism was investigated in a case-control study in which 312 patients with histologically verified bladder cancer were compared with 254 hospital controls; 13.5% of the cases but only 7.1% of controls were homozygous for the 81C-variant of this polymorphism [odds ratio (OR), 2.04; 95% confidence interval (CI), 1.15–3.61; P = 0.014]. The homozygous 81C genotype was overrepresented, particularly in the patient groups with poorly differentiated tumors (n = 145, G3; OR, 2.22; 95% CI, 1.15–4.27; P = 0.017), muscle-invasive tumors (n = 107, T₂; OR, 2.65; 95% CI, 1.35–5.23; P = 0.005), and flat transitional cell carcinoma (n = 45; OR, 3.69; 95% CI, 1.60–8.51; P = 0.002). In general, 81CC occurred more frequently in advanced types of bladder cancer. We conclude that individuals harboring the homozygous 81C-genotype of the H-ras proto-oncogene are at an increased risk of bladder cancer.

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