Abstract A105: Genetic variations in sonic pathway genes as predictors of bladder cancer risk

The hedgehog (Hh) signaling pathway plays a crucial role in normal embryonic development. However, abnormal activation of the pathway later in life has been demonstrated in a variety of human diseases, including bladder cancer.

We genotyped 171 potentially functional single nucleotide polymorphisms (SNPs) and tagging SNPs among seven Sonic Hedgehog pathway-related genes in a case-control study including 803 Caucasian bladder cancer patients and 803 matched controls.

The homozygous variant genotype of a SNP located in the Intron of Gli2 (rs4848123) was associated with a significantly increased bladder cancer risk [odds ratios (OR), 4.21; 95% confidence interval (95% CI), 1.15-15.44]. Likewise, the homozygous variant genotype of a 3’ UTR SNP (rs3823720) and a SNP in the Intron (rs10951671) of GLI3 was associated with a significantly increased bladder cancer risk (OR, 1.58, 95% CI, 1.10-2.26; and OR, 1.87, 95% CI, 1.14-3.06; respectively). To assess the cumulative effects, we performed a combined unfavorable genotype analysis that included all SNPs showing at least a borderline statistical significance. We found that, compared with the low-risk reference group with less than two unfavorable genotypes, the medium-risk group with two unfavorable genotypes exhibited a 1.29-fold (0.92-1.81) increased risk and the high-risk group with more than two unfavorable genotypes exhibited a 1.92-fold (1.36-2.71) increased risk (P(trend) < 0.0001).

To our knowledge, this is the first epidemiologic study showing that sonic pathway-related genetic variants may affect bladder cancer risk individually and jointly.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):A105.