EGFR pathway polymorphisms and bladder cancer susceptibility and prognosis

Abstract

The epidermal growth factor receptor (EGFR) pathway has recently been appreciated as a central mediator of tumorigenesis and an important drug target; however, the influence of genetic variation in this pathway on bladder cancer is not understood. Pathway activation leads to cell proliferation, angiogenesis and is antiapoptotic. We sought to test the hypothesis that bladder cancer susceptibility and survival are modified by inherited variations in the sequence of the EGFR and its pathway members. We tested associations using a population-based study of 857 bladder cancer cases and 1191 controls from New Hampshire. Multifactor dimensionality reduction software was used to predict gene-gene interactions. We detected an increased risk of bladder cancer associated with variant genotypes for the single nucleotide polymorphisms EGFR_03 [adjusted odds ratio (OR) 1.7 (95% confidence interval (CI) 1.0-2.8)] and EGFR_05 [adjusted OR 1.5 (95% CI 1.0-2.1)] compared with wild-type. EGFR variants experienced longer survival than those with wild-type alleles [e.g. adjusted hazard ratio EGFR_1808 0.3 (95% CI 0.1-0.9)]. In contrast, the variant form of the ligand, EGF_04, had worse survival [adjusted hazard ratio 1.5 (95% CI 1.0-2.3)] compared with wild-type. Our findings suggest modified bladder cancer risk and survival associated with genetic variation in the EGFR pathway. Understanding these genetic influences on increased bladder cancer susceptibility and survival may help in cancer prevention, drug development and choice of therapeutic regimen.

Fig. 1.

EGFR haploview LD plot. LD plot of EGFR SNPs showed 20% LD between significant SNPs EGFR_05 and EGFR_03. This plot shows that the tested SNPs were in tagged regions of the gene with low linkage and did not measure redundant loci.

Fig. 2.

Bladder cancer survival in relation to EGFR pathway SNPs. Kaplan–Meier plots show survival by (A) EGFR_05 genotype, and (B) EGFR_1808 genotype. Hazard ratios for heterozygotes and variants compared with wild-type were calculated using Cox proportional hazards modeling with adjustment for age, gender, smoking status, stage/grade and treatment. Black lines are homozygous wild-type, light grey are homozygous variant and dark grey are heterozygous.

Fig. 3.

Level of pEGFR, EGFR and CCND1 protein in bladder tumors by genotype. Intensity of bladder tumor cells staining positively for pEGFR, EGFR and CCND1 is graphed by genotype for the EGFR_05 SNP. Staining intensity was scored on a scale of 0–4 by a single pathologist.