Hirsch Fred R, Varella-Garcia Marileila, Bunn Paul A, Di Maria Michael V, Veve Robert, Bremmes Roy M, Barón Anna E, Zeng Chan, Franklin Wilbur A
Department of Pathology, University of Colorado Health Sciences Center, Denver, CO 80262, USA.
J Clin Oncol. 2003 Oct 15;21(20):3798-807. doi: 10.1200/JCO.2003.11.069. Epub 2003 Sep 2.
The epidermal growth factor receptor (EGFR) is frequently overexpressed in non-small-cell lung carcinoma (NSCLC), and EGFR inhibitors are promising new therapeutic agents. The molecular mechanisms responsible for EGFR overexpression are poorly understood.
Gene copy number and protein status of EGFR were investigated in microarrayed tumors from 183 NSCLC patients, including squamous cell carcinoma (SCC; 89 patients) and non-SCC (94 patients) histologies. Protein expression was assessed by immunohistochemistry on a scale from 0 to 400 (percentage of positive cells x staining intensity). Gene and chromosome 7 copy numbers were identified by fluorescent in situ hybridization (FISH).
EGFR protein overexpression was observed in 62% of the NSCLC (25% scored 201 to 300; 37% scored 301 to 400), more frequently in SCC than non-SCC (82% v 44%; P <.001), and in 80% of the bronchioloalveolar carcinomas. The prevalent FISH patterns were balanced disomy (40%) and trisomy (38%) for EGFR gene and chromosome 7 (40%), whereas balanced polysomy was seen in 13% and gene amplification was seen in 9% of the patients. Gene copy number correlated with protein expression (r = 0.4; P <.001). EGFR overexpression or high gene copy numbers had no significant influence on prognosis.
EGFR overexpression is frequent in NSCLC, is most prominent in SCC, and correlates with increased gene copy number per cell. High gene copy numbers per cell showed a trend toward poor prognosis. It will be important to evaluate EGFR gene and EGFR protein status and signal protein expression to properly interpret future clinical trials using EGFR inhibitors.
表皮生长因子受体（EGFR）在非小细胞肺癌（NSCLC）中经常过度表达，EGFR抑制剂是有前景的新型治疗药物。导致EGFR过度表达的分子机制尚不清楚。
对183例NSCLC患者的微阵列肿瘤进行研究，包括鳞状细胞癌（SCC；89例患者）和非SCC（94例患者）组织学类型。通过免疫组织化学评估蛋白质表达，范围为0至400（阳性细胞百分比×染色强度）。通过荧光原位杂交（FISH）鉴定基因和7号染色体的拷贝数。
在62%的NSCLC中观察到EGFR蛋白过度表达（25%评分为201至300；37%评分为301至400），SCC中比非SCC更常见（82%对44%；P<.001），在80%的细支气管肺泡癌中也有。EGFR基因和7号染色体最常见的FISH模式是平衡二体性（40%）和三体性（38%）（40%），而13%的患者出现平衡多体性，9%的患者出现基因扩增。基因拷贝数与蛋白质表达相关（r = 0.4；P<.001）。EGFR过度表达或高基因拷贝数对预后无显著影响。
EGFR过度表达在NSCLC中很常见，在SCC中最为突出，并且与每个细胞中基因拷贝数增加相关。每个细胞高基因拷贝数显示出预后不良的趋势。评估EGFR基因、EGFR蛋白状态和信号蛋白表达对于正确解释未来使用EGFR抑制剂的临床试验将很重要。
