Zhang Wu, Park David J, Lu Bo, Yang Dong Yun, Gordon Michael, Groshen Susan, Yun Jim, Press Oliver A, Vallböhmer Daniel, Rhodes Katrin, Lenz Heinz-Josef
Division of Medical Oncology and Department of Preventive Medicine, University of Southern California/Norris Comprehensive Cancer Center, Keck School of Medicine, Los Angeles, CA, USA.
Clin Cancer Res. 2005 Jan 15;11(2 Pt 1):600-5.
An association between epidermal growth factor receptor (EGFR) signaling pathway and response of cancer cells to ionizing radiation has been reported. Recently, a polymorphic variant in the EGFR gene that leads to an arginine-to-lysine substitution in the extracellular domain at codon 497 within subdomain IV of EGFR has been identified. The variant EGFR (HER-1 497K) may lead to attenuation in ligand binding, growth stimulation, tyrosine kinase activation, and induction of proto-oncogenes myc, fos, and jun. A (CA)(n) repeat polymorphism in intron 1 of the EGFR gene that alters EGFR expression in vitro and in vivo has also been described. In the current pilot study, we assessed both polymorphisms in 59 patients with locally advanced rectal cancer treated with adjuvant or neoadjuvant chemoradiation therapy using PCR-RFLP and a 5'-end [gamma-(33)P]ATP-labeled PCR protocol. We tested whether either polymorphism alone or in combination can be associated with local recurrence in the setting of chemoradiation treatment. We found that patients with HER-1 497 Arg/Arg genotype or lower number of CA repeats (both alleles <20) tended to have a higher risk of local recurrence (P = 0.24 and 0.31, respectively). Combined analysis showed the highest risk for local recurrence was seen in patients who possessed both a HER-1 497 Arg allele and <20 CA repeats (P = 0.05, log-rank test). Our data suggest that the HER-1 R497K and EGFR intron 1 (CA)(n) repeat polymorphisms may be potential indicators of radiosensitivity in patients with rectal cancer treated with chemoradiation.
据报道，表皮生长因子受体（EGFR）信号通路与癌细胞对电离辐射的反应之间存在关联。最近，已鉴定出EGFR基因中的一种多态性变体，该变体导致EGFR第IV亚结构域密码子497处的细胞外结构域发生精氨酸到赖氨酸的替换。变体EGFR（HER-1 497K）可能导致配体结合、生长刺激、酪氨酸激酶激活以及原癌基因myc、fos和jun的诱导减弱。还描述了EGFR基因内含子1中的（CA）（n）重复多态性，其在体外和体内均可改变EGFR表达。在当前的初步研究中，我们使用PCR-RFLP和5'-末端[γ-（33）P]ATP标记的PCR方案，对59例接受辅助或新辅助放化疗的局部晚期直肠癌患者的两种多态性进行了评估。我们测试了单独或联合的任何一种多态性是否与放化疗情况下的局部复发相关。我们发现，具有HER-1 497 Arg/Arg基因型或CA重复次数较少（两个等位基因均<20）的患者往往有更高的局部复发风险（分别为P = 0.24和0.31）。联合分析显示，同时具有HER-1 497 Arg等位基因和<20个CA重复的患者局部复发风险最高（P = 0.05，对数秩检验）。我们的数据表明，HER-1 R497K和EGFR内含子1（CA）（n）重复多态性可能是接受放化疗的直肠癌患者放射敏感性的潜在指标。
