Abstract PR-09: Genetic variations in the sonic hedgehog pathway and clinical outcomes in bladder cancer

Abstract

Abstract The sonic hedgehog (Shh) pathway plays an important role in embryonic development and stem cell maintenance. Abnormal activation of Shh pathway has been implicated in the development of various cancers, and also in the progression to metastatic disease. We hypothesized that genetic variations in the Shh pathway may affect bladder cancer (BC) patients' clinical outcomes. We evaluated the association of 151 SNPs in nine Shh genes in a follow-up study of 738 bladder cancer patients for recurrence and progression risk in superficial BC patients, and survival in muscle-invasive and metastasis (MiM) BC patients. In superficial BC patients, GLI2 variants rs11685068 (HR: 2.12, 95% CI: 1.44–3.12) and rs7605011 (HR:1.94, 95% CI: 1.33–2.85) were significantly associated with higher recurrence risk. Individuals with rs11685068 (median survival time (MST): 7.3 months, Log-Rank P: 0.004) and rs7605011 (MST: 7.6 months, Log-Rank P: 0.002) variant alleles had shorter recurrence-free median survival time compared to patients with wild-type genotypes (MST: 16.7 months). In the subgroup receiving Bacillus Calmette-Guérin treatment, GLI3 variants rs6463089 (HR: 2.30, 95% CI: 1.44–3.66) and rs3801192 (HR: 2.57, 95% CI: 1.48–4.46) were significantly associated with higher recurrence risk and shorter recurrence-free survival durations. We also explored the cumulative effect of multiple SNPs and higher-order gene-gene interactions in modulating the recurrence. No significant associations were observed in the progression and survival analysis after correcting for multiple testing. This is the first study to evaluate the role of germline genetic variations in Shh pathway as predictors of bladder cancer outcomes. These findings warrant further replication in independent populations to identify BC patients at a high risk for a poor outcome and prognosis. Citation Information: Cancer Prev Res 2010;3(1 Suppl):PR-09.