Sholl Lynette M, Yeap Beow Y, Iafrate A John, Holmes-Tisch Alison J, Chou Yi-Ping, Wu Ming-Tsang, Goan Yih-Gang, Su Li, Benedettini Elisa, Yu Jian, Loda Massimo, Jänne Pasi A, Christiani David C, Chirieac Lucian R
Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
Cancer Res. 2009 Nov 1;69(21):8341-8. doi: 10.1158/0008-5472.CAN-09-2477. Epub 2009 Oct 13.
In a subset of lung adenocarcinomas, the epidermal growth factor receptor (EGFR) is activated by kinase domain mutations and/or gene amplification, but the interaction between the two types of abnormalities is complex and unclear. For this study, we selected 99 consecutive never-smoking women of East Asian origin with lung adenocarcinomas that were characterized by histologic subtype. We analyzed EGFR mutations by PCR-capillary sequencing, EGFR copy number abnormalities by fluorescence and chromogenic in situ hybridization and quantitative PCR, and EGFR expression by immunohistochemistry with both specific antibodies against exon 19 deletion-mutated EGFR and total EGFR. We compared molecular and clinicopathologic features with disease-free survival. Lung adenocarcinomas with EGFR amplification had significantly more EGFR exon 19 deletion mutations than adenocarcinomas with disomy, and low and high polysomy (100% versus 54%, P = 0.009). EGFR amplification occurred invariably on the mutated and not the wild-type allele (median mutated/wild-type ratios 14.0 versus 0.33, P = 0.003), was associated with solid histology (P = 0.008), and advanced clinical stage (P = 0.009). EGFR amplification was focally distributed in lung cancer specimens, mostly in regions with solid histology. Patients with EGFR amplification had a significantly worse outcome in univariate analysis (median disease-free survival, 16 versus 31 months, P = 0.01) and when adjusted for stage (P = 0.027). Lung adenocarcinomas with EGFR amplification have a unique association with exon 19 deletion mutations and show distinct clinicopathologic features associated with a significantly worsened prognosis. In these cases, EGFR amplification is heterogeneously distributed, mostly in areas with a solid histology.
在一部分肺腺癌中，表皮生长因子受体（EGFR）通过激酶结构域突变和/或基因扩增而被激活，但这两种异常之间的相互作用复杂且尚不清楚。在本研究中，我们选取了99名连续的东亚裔从不吸烟的女性肺腺癌患者，这些患者以组织学亚型为特征。我们通过PCR-毛细管测序分析EGFR突变，通过荧光和显色原位杂交以及定量PCR分析EGFR拷贝数异常，并使用针对外显子19缺失突变型EGFR和总EGFR的特异性抗体通过免疫组织化学分析EGFR表达。我们比较了分子和临床病理特征与无病生存期的关系。与二倍体以及低和高多体性的腺癌相比，具有EGFR扩增的肺腺癌具有明显更多的EGFR外显子19缺失突变（100%对54%，P = 0.009）。EGFR扩增总是发生在突变等位基因而非野生型等位基因上（突变/野生型比值中位数分别为14.0对0.33，P = 0.003），与实体组织学相关（P = 0.008），并与临床晚期相关（P = 0.009）。EGFR扩增在肺癌标本中呈局灶性分布，主要分布在实体组织学区域。在单因素分析中，EGFR扩增的患者预后明显更差（无病生存期中位数，16个月对31个月，P = 0.01），调整分期后也是如此（P = 0.027）。具有EGFR扩增的肺腺癌与外显子19缺失突变有独特关联，并显示出与预后明显恶化相关的独特临床病理特征。在这些病例中，EGFR扩增呈异质性分布，主要分布在实体组织学区域。
