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Gender-Related Survival Differences Associated with EGFR Polymorphisms in Metastatic Colon Cancer

¹ Division of Medical Oncology and ² Department of Preventive Medicine, University of Southern California/Norris Comprehensive Cancer Center, Keck School of Medicine, Los Angeles, California

Requests for reprints: Heinz-Josef Lenz, University of Southern California/Norris Comprehensive Cancer Center, Keck School of Medicine, 1441 Eastlake Avenue, Suite 3456, Los Angeles, CA 90033. Phone: 323-865-3955; Fax: 323-865-0061; E-mail: lenz{at}usc.edu.

Key Words: Colon cancer • EGFR • gender • polymorphisms • clinical outcome

Evidence is accumulating supporting gender-related differences in the development of colonic carcinomas. Sex steroid hormone receptors are expressed in the colon and interact with epidermal growth factor receptor (EGFR), a gene widely expressed in colonic tissue. Increased EGFR expression is linked with poor prognosis in colon cancer. Within the EGFR gene there are two functional polymorphisms of interest: a polymorphism located at codon 497 (HER-1 R497K) and a dinucleotide (CA)_n repeat polymorphism located within intron 1. These germ-line polymorphisms of EGFR were analyzed in genomic DNA from 318 metastatic colon cancer patients, 177 males and 141 females, collected from 1992 to 2003. Gender-related survival differences were associated with the HER-1 R497K polymorphism (P_interaction = 0.003). Females with the HER-1 497 Arg/Arg variant had better overall survival (OS) when compared with the Lys/Lys and/or Lys/Arg variants. In males the opposite was true. The EGFR dinucleotide (CA)_n repeat also trended with a gender-related OS difference (P_interaction = 0.11). Females with both short <20 (CA)_n repeat alleles had better OS than those with any long 20 (CA)_n repeats. In males the opposite was true. Combination analysis of the two polymorphisms taken together also revealed the same gender-related survival difference (P_interaction = 0.002). These associations were observed using multivariable analysis. The two polymorphisms were not in linkage disequilibrium and are independent of one another. This study supports the role of functional EGFR polymorphisms as independent prognostic markers in metastatic colon cancer. As a prognostic factor, these variants had opposite prognostic implications based on gender. [Cancer Res 2008;68(8):3037–42]