Franco-Hernandez Carmen, Martinez-Glez Victor, Arjona Dolores, de Campos Jose M, Isla Alberto, Gutierrez Manuel, Vaquero Jesus, Rey Juan A
Molecular Oncogenetics Laboratory, Research Unit, University Hospital La Paz, Paseo Castellana 261, 28046 Madrid, Spain.
Cancer Genet Cytogenet. 2007 Feb;173(1):63-7. doi: 10.1016/j.cancergencyto.2006.09.023.
Clinical response to Gefitinib (Iressa, ZD1839) has been found to be associated with somatic mutations, primarily of exons 18-21, of the epidermal growth factor receptor gene (EGFR) in non-small cell lung cancer (NSCLC). Evidence of a positive response was also reported recently on a patient with brain metastasis from NSCLC. On the other hand, amplification of EGFR appears to be associated with a poor prognosis. To determine whether EGFR mutations and amplification are involved in the tumorigenesis of brain metastases, we performed polymerase chain reaction/single-strand conformation polymorphism to examine exons 1, 2, and 7-26 of EGFR in a series of 18 brain metastases. The metastases derived from malignant melanoma (three cases), lung carcinoma (six cases), breast carcinoma (three cases), ovarian carcinoma (two cases), and one each from colon, kidney, bladder, and undifferentiated carcinoma. In addition to several sequence polymorphisms, we identified two mutations on E19 consisting of 18-base pair (bp) deletions: 2423-24440del and 2426-2443del. These mutations presented in lesions derived from kidney carcinoma and lung adenocarcinoma. By real-time quantitaive polymerase chain reaction technique, we determined the amplification/overdose status of EGFR by analyzing exons 11 and 25. Amplification (5- to 100-fold) was identified in three tumors, and overdose (low-level gene amplification corresponding to increases of 1- to 5-fold) presented in four additional metastases. These findings suggest that EGFR mutations and polymorphisms are not exclusively present in metastases derived from lung carcinoma. Accordingly, targeting of EGFR to determine molecular alterations of this gene may be useful in the management of patients with brain metastases.
已发现吉非替尼（易瑞沙，ZD1839）的临床反应与非小细胞肺癌（NSCLC）中表皮生长因子受体基因（EGFR）的体细胞突变相关，主要是外显子18 - 21的突变。最近也有报告称一名NSCLC脑转移患者出现了阳性反应的证据。另一方面，EGFR的扩增似乎与预后不良有关。为了确定EGFR突变和扩增是否参与脑转移瘤的发生，我们进行了聚合酶链反应/单链构象多态性分析，以检测18例脑转移瘤系列中EGFR的外显子1、2以及7 - 26。这些转移瘤分别来源于恶性黑色素瘤（3例）、肺癌（6例）、乳腺癌（3例）、卵巢癌（2例），以及各1例来自结肠、肾脏、膀胱和未分化癌的转移瘤。除了几个序列多态性外，我们在E19上鉴定出两个由18个碱基对（bp）缺失组成的突变：2423 - 24440del和2426 - 2443del。这些突变出现在来源于肾癌和肺腺癌的病灶中。通过实时定量聚合酶链反应技术，我们通过分析外显子11和25来确定EGFR的扩增/过量状态。在三个肿瘤中鉴定出扩增（5至100倍），在另外四个转移瘤中出现过量（对应于1至5倍增加的低水平基因扩增）。这些发现表明EGFR突变和多态性并非仅存在于来源于肺癌的转移瘤中。因此，针对EGFR来确定该基因的分子改变可能有助于脑转移患者的管理。
