HER family receptor abnormalities in lung cancer brain metastases and corresponding primary tumors.
HER family receptor abnormalities in lung cancer brain metastases and corresponding primary tumors.
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DOI：
10.1158/1078-0432.ccr-08-2921
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发表时间：
2009-08-01
期刊：
影响因子：
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通讯作者：
Wistuba II
中科院分区：
文献类型：
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作者：
Sun M;Behrens C;Feng L;Ozburn N;Tang X;Yin G;Komaki R;Varella-Garcia M;Hong WK;Aldape KD;Wistuba II
目的：比较非小细胞肺癌(NSCLC)原发灶和脑转移灶中HER受体及其配体表达的特点。应用免疫组织化学方法检测55例非小细胞肺癌原发肿瘤(PT)和相应的脑转移瘤(BM)组织中表皮生长因子受体(EGFR)、磷酸化(P)-EGFR、HER2、HER3和p-HER3及其配体表皮生长因子、转化生长因子-α、双调节蛋白、表调节蛋白、β细胞蛋白、肝素结合的表皮生长因子样生长因子、神经调节蛋白-1和-2的表达。用荧光原位杂交法分析EGFR拷贝数，用聚合酶链式反应测序分析突变。在转移瘤中，表皮生长因子(细胞膜，BM 161.5 vs PT 48.5；P=0.027；胞核，BM 92.2 vs 67.4；P=0.008)、两性调节蛋白(胞核，BM 53.7 vs PT 33.7；P=0.019)、p-EGFR(胞膜，BM 161.5 vs PT 76.0；P<；0.0001；胞浆，BM 101.5 vs PT 55.9；P=0.014)和p-HER3(胞膜，BM 25.0 vs PT 3.7；P=0.001)高于原发肿瘤(PT)。原发肿瘤胞浆转化生长因子-α表达显著高于骨髓(PT 149.8 vs BM 111.3；P=0.008)和NeuRegin-1(PT 158.5 vs BM 122.8；P=0.006)。在腺癌中，原发灶(65%)和脑转移灶(63%)的EGFR拷贝数增加(高多倍体和扩增)的频率类似。然而，腺癌转移瘤(30%)的EGFR扩增频率高于相应的原发癌(10%)。原发肿瘤显示EGFR扩增的患者倾向于在较早的时间点发生脑转移。我们的研究结果表明，非小细胞肺癌脑转移瘤在其家族受体相关异常方面与原发肺肿瘤有显著差异。
To compare the characteristics of HER receptors and their ligands deregulation between primary tumor and corresponding brain metastases of non-small cell lung carcinoma (NSCLC). Fifty five NSCLC primary tumors (PT) and corresponding brain metastases (BM) specimens were examined for the immunohistochemical expression of EGFR, phosphorylated (p)–EGFR, Her2, Her3, and p-Her3, and their ligands EGF, TGF-α, amphiregulin, epiregulin, betacellulin, heparin-binding EGFR-like growth factor, and neuregulins-1 and -2. Analysis of EGFR copy number using fluorescent in situ hybridization and mutation by PCR-based sequencing was also performed. Metastases showed significantly higher immunohistochemical expression of EGF (membrane, BM 66.0 vs. PT 48.5; P=0.027; and nucleus, BM 92.2 vs. 67.4; P=0.008), amphiregulin (nucleus, BM 53.7 vs. PT 33.7; P=0.019), p-EGFR (membrane, BM 161.5 vs. PT 76.0; P<0.0001; and cytoplasm, BM 101.5 vs. PT 55.9; P=0.014), and p-Her3 (membrane, BM 25.0 vs. PT 3.7; P=0.001) than primary tumors (PT) did. Primary tumors showed significantly higher expression of cytoplasmic TGF–α (PT 149.8 vs. BM 111.3; P=0.008) and neuregulin-1 (PT 158.5 vs. BM 122.8; P=0.006). In adenocarcinomas, a similar high frequency of EGFR copy number gain (high polysomy and amplification) was detected in primary (65%) and brain metastasis (63%) sites. However, adenocarcinoma metastases (30%) showed higher frequency of EGFR amplification than corresponding primary tumors (10%). Patients whose primary tumors showed EGFR amplification tended to develop brain metastases at an earlier time points. Our findings suggest that NSCLC brain metastases have some significant differences in HER family receptors-related abnormalities from primary lung tumors.