Homogeneous EGFR amplification defines a subset of aggressive Barrett's adenocarcinomas with poor prognosis
Homogeneous EGFR amplification defines a subset of aggressive Barrett's adenocarcinomas with poor prognosis
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DOI：
10.1111/j.1365-2559.2010.03643.x
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发表时间：
2010-09-01
期刊：
影响因子：
6.4
通讯作者：
Sauter, Guido
中科院分区：
文献类型：
--
作者：
Marx, Andreas H.;Zielinski, Margarete;Sauter, Guido
目的：表皮生长因子受体（EGFR）是一种酪氨酸激酶（TK），参与许多癌症类型的肿瘤进展，可作为重要的治疗靶点（厄洛替尼、西妥昔单抗）。EGFR扩增和表达的异质性可能代表抗EGFR治疗的主要缺点。本研究的目的是确定肿瘤异质性对巴雷特腺癌（BAC）抗EGFR治疗的潜在影响。方法和结果：使用荧光原位杂交（FISH）和免疫组织化学（MHC）分析了112例BAC和45例淋巴结转移瘤的组织微阵列（TMA）切片的EGFR扩增和表达。还对20个样本的子集进行EGFR外显子18-21和Kirsten大鼠肉瘤病毒癌基因同源物（KRAS）外显子2-3突变测序。在112个可解释的BAC中的7个（6.25%）中观察到EGFR扩增，并且通常高水平，每个肿瘤细胞具有超过10-20个EGFR拷贝（EGFR/着丝粒7比率> 3）。EGFR扩增与高pT、pN和预后不良相关（P = 0.0004）。在29例原发性肿瘤和29例匹配的淋巴结转移瘤中发现了相同的EGFR扩增状态。此外，对所有扩增的BAC和相应的淋巴结转移的3至16个大切片的FISH分析未显示EGFR扩增的任何异质性。未发现EGFR突变，但发现1个KRAS突变。结论：原发肿瘤和转移瘤中EGFR扩增的高水平和均一性提示抗EGFR药物在BAC中具有潜在的治疗价值。
Aims:The epidermal growth factor receptor (EGFR) is a tyrosine kinase (TK) involved in the tumour progression of many cancer types and may serve as an important therapeutic target (erlotinib, cetuximab). Heterogeneity of EGFR amplification and expression could represent a major drawback for anti-EGFR therapy. The aim of this study was performed to determine the potential impact of tumour heterogeneity on anti-EGFR therapy in Barrett's adenocarcinoma (BAC).Methods and results:Tissue microarray (TMA) sections of 112 BAC and 45 lymph node metastases were analysed for EGFR amplification and expression using fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC). A subset of 20 samples was also sequenced for EGFR exons 18-21 and Kirsten rat sarcoma viral oncogene homologue (KRAS) exons 2-3 mutations. EGFR amplification was seen in seven (6.25%) of 112 interpretable BAC and typically high-level with more than 10-20 EGFR copies per tumour cell (EGFR/centromere 7 ratio > 3). EGFR amplification was associated with high pT, pN and poor prognosis (P = 0.0004). Identical EGFR amplification status was found in 29 primary tumours and 29 matched lymph node metastases. Moreover, FISH analysis of three to 16 large sections from all amplified BAC and corresponding lymph node metastases did not reveal any heterogeneity of EGFR amplification. No EGFR mutation but one KRAS mutation was found.Conclusion:The high level and homogeneity of EGFR amplification in primary tumours and metastases suggests the potential therapeutic utility of anti-EGFR drugs in BAC.