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Epidermal Growth Factor Receptor R497K Polymorphism Is a Favorable Prognostic Factor for Patients with Colorectal Carcinoma

Authors' Affiliations: ¹ National Yang-Ming University School of Medicine; ² Division of Oncology and Hematology, Department of Medicine and ³ Division of Colorectal Surgery, Department of Surgery, Taipei Veterans General Hospital; and ⁴ Institute of Biopharmaceutical Science, College of Life Science, National Yang-Ming University, Taipei, Taiwan, Republic of China

Requests for reprints: Yeu Su, Institute of Biopharmaceutical Science, College of Life Science, National Yang-Ming University, Taipei, Taiwan, Republic of China. Phone: 886-2-2826-7143; Fax: 886-2-2825-0883; E-mail: yeusu{at}ym.edu.tw.

Purpose: It has been shown that the R497K polymorphism of the epidermal growth factor receptor (EGFR) has attenuated functions in ligand binding, tyrosine kinase activation, and growth stimulation. Because the activation of EGFR results in an unfavorable prognosis of patients with colorectal carcinoma, a pilot study was conducted to assess the influence of this polymorphism on colorectal carcinoma patients.

Experimental Design: We retrospectively analyzed the effect of the R497K polymorphism of EGFR on clinicopathologic features in 209 colorectal carcinoma patients, including 100 with stage II/III colorectal carcinoma receiving curative surgery and the other 109 with metastatic diseases.

Results: An excellent correlation in codon 497 statuses examined by patients' WBCs and tumor tissues was found but no significant between-group difference in patients with or without colorectal carcinoma (P = 0.97). A marked decrease on EGFR phosphorylation (P < 0.01) and c-Myc activation (P = 0.02) was observed in patients with R497K polymorphism, which is associated with decreased invasion (P = 0.01), lower nodal involvement (P = 0.02), reduced subsequent metastasis (P < 0.01), and longer disease-free (P < 0.01) as well as overall (P < 0.01) survival in stage II/III colorectal carcinoma patients who had received curative surgery. For patients with metastatic colorectal carcinoma, this polymorphism was associated with a higher response to 5-fluorouracil/oxaliplatin treatment (P = 0.02) and a longer survival (P < 0.01). By multivariate analysis, this polymorphism was also identified as an independent prognostic factor (P = 0.03).

Conclusions: These data suggest that the R497K polymorphism of the EGFR, by reducing its activation and a consequential down-regulation of its target genes, could be a key determinant for reduced tumor recurrence of stage II/III colorectal carcinoma patients receiving curative surgery and a longer survival of patients with stage II/III as well as metastatic colorectal carcinoma.