Genetic heterogeneity of the epidermal growth factor receptor in non-small cell lung cancer cell lines revealed by a rapid and sensitive detection system, the peptide nucleic acid-locked nucleic acid PCR clamp
Genetic heterogeneity of the epidermal growth factor receptor in non-small cell lung cancer cell lines revealed by a rapid and sensitive detection system, the peptide nucleic acid-locked nucleic acid PCR clamp
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DOI：
10.1158/0008-5472.can-05-0331
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发表时间：
2005-08-15
期刊：
影响因子：
11.2
通讯作者：
Hagiwara, K
中科院分区：
文献类型：
--
作者：
Nagai, Y;Miyazawa, H;Hagiwara, K
肺癌是世界范围内癌症死亡的主要原因之一。吉非替尼是表皮生长因子受体（EGFR）酪氨酸激酶活性的抑制剂，已被引入晚期肺癌的治疗中。对吉非替尼的反应性与EGFR突变的存在有关。临床样品除了癌细胞之外还含有许多正常细胞。能够在野生型EGFR基因的大背景中检测EGFR突变的方法可以提供上级临床测试。我们开发了一种快速灵敏的EGFR突变检测系统，命名为肽核酸锁核酸（PNA-LNA）PCR钳，可以在野生型EGFR的100- 1,000倍背景下检测EGFR突变。我们用这种方法筛选了30个从日本患者中建立的非小细胞肺癌细胞系。除了11个具有突变的细胞系之外，我们还发现了12个细胞系，其中仅在细胞亚群中观察到特定突变。EGFR的遗传异质性表明EGFR基因在已确定的癌症中是不稳定的，并且异质性可以解释肺癌对吉非替尼的可变临床应答。
Lung cancer is one of the leading causes of the cancer death worldwide. Gefitinib is an inhibitor of the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) and has been introduced in the treatment of advanced lung cancers. The responsiveness to gefitinib has been linked to the presence of EGFR mutations. Clinical samples contain many normal cells in addition to cancer cells. A method capable of detecting EGFR mutations in a large background of wild-type EGFR genes could provide a superior clinical test. We developed a rapid and sensitive detection system for EGFR mutations named the peptide nucleic acid-locked nucleic acid (PNA-LNA) PCR clamp that can detect EGFR mutations in the presence of 100-to 1,000-fold background of wild-type EGFR. We used this method to screen 30 non-small cell lung cancer cell lines established from Japanese patients. In addition to 11 cell lines that have mutations, we found 12 cell lines in which specific mutations are observed only in the subpopulation(s) of the cells. Genetic heterogeneity of EGFR suggests that the EGFR gene is unstable in established cancers and the heterogeneity may explain variable clinical responses of lung cancers to gefitinib.