Genetic variations in the sonic hedgehog pathway affect clinical outcomes in non-muscle-invasive bladder cancer

Cancer Prev Res (Phila). 2010 Oct;3(10):1235-45. doi: 10.1158/1940-6207.CAPR-10-0035. Epub 2010 Sep 21.

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 wild-type genotype of either of these SNPs was associated with a lower recurrence rate and longer recurrence-free 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Aged
  • Antineoplastic Agents / therapeutic use
  • BCG Vaccine / therapeutic use
  • Carcinoma, Transitional Cell / genetics*
  • Carcinoma, Transitional Cell / pathology
  • Carcinoma, Transitional Cell / therapy
  • Case-Control Studies
  • Drug Resistance, Neoplasm / genetics
  • Female
  • Genetic Predisposition to Disease*
  • Genotype
  • Hedgehog Proteins / genetics*
  • Humans
  • Kaplan-Meier Estimate
  • Male
  • Middle Aged
  • Neoplasm Recurrence, Local / genetics
  • Neoplasm Recurrence, Local / pathology
  • Neoplasm Staging
  • Polymorphism, Single Nucleotide
  • Treatment Outcome
  • Urinary Bladder Neoplasms / genetics*
  • Urinary Bladder Neoplasms / pathology
  • Urinary Bladder Neoplasms / therapy

Substances

  • Antineoplastic Agents
  • BCG Vaccine
  • Hedgehog Proteins