Wang Wei-Shu, Chen Po-Min, Chiou Tzeon-Jye, Liu Jin-Hwang, Lin Jen-Kou, Lin Tzu-Chen, Wang Huann-Sheng, Su Yeu
National Yang-Ming University School of Medicine, Taipei, Taiwan, Republic of China.
Clin Cancer Res. 2007 Jun 15;13(12):3597-604. doi: 10.1158/1078-0432.CCR-06-2601.
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.
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.
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).
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.
研究表明，表皮生长因子受体（EGFR）的R497K多态性在配体结合、酪氨酸激酶激活和生长刺激方面功能减弱。由于EGFR的激活会导致结直肠癌患者预后不良，因此开展了一项初步研究以评估该多态性对结直肠癌患者的影响。
我们回顾性分析了EGFR的R497K多态性对209例结直肠癌患者临床病理特征的影响，其中包括100例接受根治性手术的II/III期结直肠癌患者和另外109例转移性疾病患者。
通过患者白细胞和肿瘤组织检测的497密码子状态具有良好的相关性，但结直肠癌患者与非结直肠癌患者之间无显著组间差异（P = 0.97）。在具有R497K多态性的患者中观察到EGFR磷酸化（P < 0.01）和c-Myc激活（P = 0.02）显著降低，这与侵袭减少（P = 0.01）、淋巴结受累降低（P = 0.02）、后续转移减少（P < 0.01）以及接受根治性手术的II/III期结直肠癌患者更长的无病生存期（P < 0.01）和总生存期（P < 0.01）相关。对于转移性结直肠癌患者，这种多态性与对5-氟尿嘧啶/奥沙利铂治疗的更高反应率（P = 0.02）和更长生存期（P < 0.01）相关。通过多因素分析，这种多态性也被确定为独立的预后因素（P = 0.03）。
这些数据表明，EGFR的R497K多态性通过降低其激活及其靶基因的相应下调，可能是接受根治性手术的II/III期结直肠癌患者肿瘤复发减少以及II/III期和转移性结直肠癌患者生存期延长的关键决定因素。
