TY - JOUR
T1 - Genetic variations in the sonic hedgehog pathway affect clinical outcomes in non-muscle-invasive bladder cancer
AU - Chen, Meng
AU - Hildebrandt, Michelle A.T.
AU - Clague, Jessica
AU - Kamat, Ashish M.
AU - Picornell, Antoni
AU - Chang, Joshua
AU - Zhang, Xiaofan
AU - Izzo, Julie
AU - Yang, Hushan
AU - Lin, Jie
AU - Gu, Jian
AU - Chanock, Stephen
AU - Kogevinas, Manolis
AU - Rothman, Nathaniel
AU - Silverman, Debra T.
AU - Garcia-Closas, Montserrat
AU - Barton Grossman, H.
AU - Dinney, Colin P.
AU - Malats, Núria
AU - Wu, Xifeng
PY - 2010/10
Y1 - 2010/10
N2 - 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.
AB - 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.
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U2 - 10.1158/1940-6207.CAPR-10-0035
DO - 10.1158/1940-6207.CAPR-10-0035
M3 - Article
C2 - 20858759
AN - SCOPUS:77958611363
SN - 1940-6207
VL - 3
SP - 1235
EP - 1245
JO - Cancer Prevention Research
JF - Cancer Prevention Research
IS - 10
ER -