Carcinogenesis Advance Access originally published online on April 16, 2009
Carcinogenesis 2009 30(7):1155-1160; doi:10.1093/carcin/bgp077
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EGFR pathway polymorphisms and bladder cancer susceptibility and prognosis
Section of Biostatistics and Epidemiology, Department of Community and Family Medicine, Dartmouth Medical School, One Medical Center Drive, Lebanon, NH 03756, USA
1 Department of Community Health/Epidemiology
2 Department of Pathology and Laboratory Medicine, Center for Environmental Health and Technology, Brown University, Providence, RI 02912, USA
3 Department of Pathology, Dartmouth Medical School, One Medical Center Drive, Lebanon, NH 03756, USA
* To whom correspondence should be addressed. Dartmouth Medical School, 7927 Rubin 860, One Medical Center Drive, Lebanon, NH 03756, USA. Tel: +1 603 653 9019; Fax: +1 603 653 9093; Email: angeline.andrew{at}dartmouth.edu
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.
Abbreviations: CCND1, cyclin D1; CI, confidence interval; EGF, epidermal growth factor; EGFR, epidermal growth factor receptor; LD, linkage disequilibruim; MDR, multifactor dimensionality reduction; OR, odds ratio; SNP, single nucleotide polymorphism; VEGF, vascular endothelial growth factor
Received October 27, 2008; revised March 26, 2009; accepted March 28, 2009.