Mutations of the epidermal growth factor receptor gene in lung cancer:: Biological and clinical implications
Mutations of the epidermal growth factor receptor gene in lung cancer:: Biological and clinical implications
复制标题
DOI：
10.1158/0008-5472.can-04-2818
复制
发表时间：
2004-12-15
期刊：
影响因子：
11.2
通讯作者：
Mitsudomi, T
中科院分区：
文献类型：
--
作者：
Kosaka, T;Yatabe, Y;Mitsudomi, T
最近有报道称，表皮生长因子受体（EGFR）基因酪氨酸激酶结构域的突变发生在肺癌患者亚群中，这些患者对EGFR酪氨酸激酶抑制剂表现出显著的反应。为了进一步了解EGFR在肺癌发生中的作用，我们使用从未选择的277例接受手术切除的肺癌患者中提取的总RNA对酪氨酸激酶结构域的18-21外显子进行了测序，并将结果与临床和病理特征相关联。111例（40%）患者存在EGFR突变。52例为第19外显子746 ~ 750密码子附近的帧内缺失，54例为点突变，其中49例位于第21外显子858密码子，4例位于第18外显子719密码子，5例为主要位于第20外显子的重复/插入。它们在女性（P < 0.001）、腺癌（P = 0.0013）和从不吸烟者（P < 0.001）中更为常见。多因素分析显示，EGFR突变与腺癌组织学（P = 0.0012）和吸烟状况（P < 0.001）独立相关，但与女性性别无关（P = 0.9917）。在腺癌中，EGFR突变在中度分化肿瘤中更为常见（P < 0.001），但与患者年龄、疾病分期或患者生存期无关。KRAS和TP53突变分别占13%和41%。在KRAS突变的肿瘤中从未发生EGFR突变，而EGFR突变独立于TP53突变。EGFR突变定义了没有KRAS突变的肺腺癌的一个独特亚群，这不是由烟草致癌物引起的。
Recently it has been reported that mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) gene occur in, subset of patients with lung cancer showing a dramatic response to EGFR tyrosine kinase inhibitors. To gain further insights in the role of EGFR in lung carcinogenesis, we sequenced exons 18-21 of the tyrosine kinase domain using total RNA extracted from unselected 277 patients with lung cancer who underwent surgical resection and correlated the results with clinical and pathologic features. EGFR mutations were present in 111 patients (40%). Fifty-two were in-frame deletions around codons 746-750 in exon 19, 54 were point mutations including 49 at codon 858 in exon 21 and 4 at codon 719 in exon 18, and 5 were duplications/insertions mainly in exon 20. They were significantly more frequent in female (P < 0.001), adenocarcinomas (P = 0.0013), and in never-smokers (P < 0.001). Multivariate analysis suggested EGFR mutations were independently associated with adenocarcinoma histology (P = 0.0012) and smoking status (P < 0.001), but not with female gender (P = 0.9917). In adenocarcinomas, EGFR mutations were more frequent in well to moderately differentiated tumors (P < 0.001) but were independent of patient age, disease stages, or patient survival. KRAS and TP53 mutations were present in 13 and 41%, respectively. EGFR mutations never occurred in tumors with KRAS mutations, whereas EGFR mutations were independent of TP53 mutations. EGFR mutations define a distinct subset of pulmonary adenocarcinoma without KRAS mutations, which is not caused by tobacco carcinogens.