Genetic Variations in the Sonic Hedgehog Pathway Affect Clinical Outcomes in Non–Muscle-Invasive Bladder Cancer

Abstract

Sonic hedgehog (Shh) pathway genetic variations may affect bladder cancer risk and clinical outcomes. Therefore, we genotyped 177 single-nucleotide polymorphisms (SNP) in 11 Shh pathway genes in a study including 803 bladder cancer cases and 803 controls. We assessed SNP associations with cancer risk and clinical outcomes in 419 cases of non-muscle-invasive bladder cancer (NMIBC) and 318 cases of muscle-invasive and metastatic bladder cancer (MiMBC). Only three SNPs (GLI3 rs3823720, rs3735361, and rs10951671) reached nominal significance in association with risk (P ≤ 0.05), which became nonsignificant after adjusting for multiple comparisons. Nine SNPs reached a nominally significant individual association with recurrence of NMIBC in patients who received transurethral resection (TUR) only (P ≤ 0.05), of which two (SHH rs1233560 and GLI2 rs11685068) were replicated independently in 356 TUR-only NMIBC patients, with P values of 1.0 × 10 −3 (SHH rs1233560) and 1.3 × 10 −3 (GLI2 rs11685068). Nine SNPs also reached a nominally significant individual association with clinical outcome of NMIBC patients who received Bacillus Calmette-Guérin (BCG; P ≤ 0.05), of which two, the independent GLI3 variants rs6463089 and rs3801192, remained significant after adjusting for multiple comparisons (P = 2 × 10 −4 and 9 × 10 −4 , respectively). The wildtype genotype of either of these SNPs was associated with a lower recurrence rate and longer recurrencefree survival (versus the variants). Although three SNPs (GLI2 rs735557, GLI2 rs4848632, and SHH rs208684) showed nominal significance in association with overall survival in MiMBC patients (P ≤ 0.05), none remained significant after multiple-comparison adjustments. Germ-line genetic variations in the Shh pathway predicted clinical outcomes of TUR and BCG for NMIBC patients.

Clinicopathological correlates of Gli1 expression in a population-based cohort of patients with newly diagnosed bladder cancer

“…However, despite a large body of work, reliable molecular markers and reliable molecular therapeutic targets have not been identified [16]. Several recent studies have focused on the role of the hedgehog/Gli signal transduction pathway in carcinogenesis of TCC [6,7]. The hedgehog pathway operates in organogenesis, control of proliferation, and the differentiation of embryonic and adult stem cells, thus, not surprisingly, it has been linked with several different tumors.…”

“…Chen etal. [7] examined genetic variations in the hedgehog pathway in a large group of patients with bladder cancer in Texas. These investigators genotyped 177 single nucleotide polymorphisms (SNPs) in 11 hedgehog pathway genes.…”

“…However, early studies in normal urothelial cells and TCC cell lines rarely found mutations in the Ptc1 gene and little overexpression of Gli1–3, Ptc1, or Sonic Hedgehog, this lead to the conclusion that the hedgehog pathway is weakly active in normal adult urothelial cells and of limited or no importance in TCC [5]. More recent studies in urothelial cell lines and bladder tumors and genotype studies of patients with bladder cancer have led to a revaluation of the importance of hedgehog pathway signaling [6,7]. However, few of these studies have focused on the Gli1, which is thought to be the most reliable biomarker of hedgehog pathway activity [8,9], in primary human bladder tumors.…”

Hedgehog (Hh) Signaling is a Predictor of Clinical Outcome for Advanced Non-Small Cell Lung Cancer (NSCLC)

“…Meanwhile, many authors suggested that HHSP can be activated in later stages of diseases in which HHSP activation has been shown to correlate with lower RFS and bad OS [33][34][35][36][37].…”

A Strong Case for Personalized, Targeted Cancer Prevention

“…Although perhaps less advanced than this global approach in a phase-III clinical trial, genotyping work in other sites, including the colorectum (aspirin, celecoxib, statins), prostate (selenium), and bladder (BCG), is beginning to make headway toward personalized cancer prevention as well (26)(27)(28)(29). Similar personalized genotyping approaches are being applied in research in tobacco dependence (30) and cancer therapy (31).…”