title: 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 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.
authors.affiliation: Department of Epidemiology, The University of Texas M D Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Meng
authors.initials: M
authors.lastname: Chen
authors.forename: Michelle A T
authors.initials: MA
authors.lastname: Hildebrandt
authors.forename: Jessica
authors.initials: J
authors.lastname: Clague
authors.forename: Ashish M
authors.initials: AM
authors.lastname: Kamat
authors.forename: Antoni
authors.initials: A
authors.lastname: Picornell
authors.forename: Joshua
authors.initials: J
authors.lastname: Chang
authors.forename: Xiaofan
authors.initials: X
authors.lastname: Zhang
authors.forename: Julie
authors.initials: J
authors.lastname: Izzo
authors.forename: Hushan
authors.initials: H
authors.lastname: Yang
authors.forename: Jie
authors.initials: J
authors.lastname: Lin
authors.forename: Jian
authors.initials: J
authors.lastname: Gu
authors.forename: Stephen
authors.initials: S
authors.lastname: Chanock
authors.forename: Manolis
authors.initials: M
authors.lastname: Kogevinas
authors.forename: Nathaniel
authors.initials: N
authors.lastname: Rothman
authors.forename: Debra T
authors.initials: DT
authors.lastname: Silverman
authors.forename: Montserrat
authors.initials: M
authors.lastname: Garcia-Closas
authors.forename: H Barton
authors.initials: HB
authors.lastname: Grossman
authors.forename: Colin P
authors.initials: CP
authors.lastname: Dinney
authors.forename: Núria
authors.initials: N
authors.lastname: Malats
authors.forename: Xifeng
authors.initials: X
authors.lastname: Wu
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001500:BCG Vaccine / Q000627:therapeutic use; D002295:Carcinoma, Transitional Cell / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D016022:Case-Control Studies; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D053823:Hedgehog Proteins / Q000235:genetics*; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000235:genetics / Q000473:pathology; D009367:Neoplasm Staging; D020641:Polymorphism, Single Nucleotide; D016896:Treatment Outcome; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy
chemical_list: D000970:Antineoplastic Agents; D001500:BCG Vaccine; D053823:Hedgehog Proteins