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Carcinogenesis Advance Access published online on April 16, 2009
Carcinogenesis, doi:10.1093/carcin/bgp077
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© The Author 2009. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

EGFR pathway polymorphisms and bladder cancer susceptibility and prognosis

Rebecca A. Mason1, Elaine V. Morlock1, Margaret R. Karagas1, Karl T. Kelsey2, Carmen J. Marsit2, Alan R. Schned3 and Angeline S. Andrew1

1 Department of Community and Family Medicine, Section of Biostatistics and Epidemiology, Dartmouth Medical School, Lebanon, NH 03756
2 Department of Community Health/Epidemiology & Department of Pathology and Laboratory Medicine, Center for Environmental Health and Technology, Brown University, Providence, RI 02912
3 Department of Pathology, Dartmouth Medical School, Lebanon, NH 03756

Corresponding Author: Dr. Angeline S. Andrew, Dartmouth Medical School, 7927 Rubin 860, One Medical Center Drive, Lebanon, NH 03756, Telephone: (603) 653-9019 Fax: (603) 653-9093 E-mail: Angeline.Andrew{at}dartmouth.edu

Background: 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 anti-apoptotic. Objective: 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. Methods: We tested associations using a population-based study of 857 bladder cancer cases and 1192 controls from New Hampshire. Multifactor dimensionality reduction software was used to predict gene-gene interactions. Results: We detected an increased risk of bladder cancer associated with variant genotypes for the single nucleotide polymorphisms (SNPs) EGFR_03 (adjusted OR 1.7 (95%CI 1.0-2.8)) and EGFR_05 (adjusted OR 1.5 (95%CI1.0-2.1)), compared with wildtype. EGFR variants experienced longer survival than those with wildtype 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 HR 1.5 (95%CI 1.0-2.3)) compared to wildtype. Conclusion: 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.

Received October 27, 2008; revised March 26, 2009; accepted March 28, 2009.


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