Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Histopathology. 2010 Sep;57(3):418-26. doi: 10.1111/j.1365-2559.2010.03643.x. Epub 2010 Aug 31.
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).
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.
The high level and homogeneity of EGFR amplification in primary tumours and metastases suggests the potential therapeutic utility of anti-EGFR drugs in BAC.
表皮生长因子受体（EGFR）是一种酪氨酸激酶（TK），参与多种癌症类型的肿瘤进展，可能是一个重要的治疗靶点（厄洛替尼、西妥昔单抗）。EGFR 扩增和表达的异质性可能是抗 EGFR 治疗的一个主要缺点。本研究旨在确定肿瘤异质性对巴雷特腺癌（BAC）抗 EGFR 治疗的潜在影响。
使用荧光原位杂交（FISH）和免疫组织化学（IHC）分析了 112 例 BAC 和 45 例淋巴结转移的组织微阵列（TMA）切片，以检测 EGFR 扩增和表达。还对 20 例样本的 EGFR 外显子 18-21 和 Kirsten 大鼠肉瘤病毒致癌基因同源物（KRAS）外显子 2-3 突变进行了测序。在 112 个可解释的 BAC 中有 7 个（6.25%）观察到 EGFR 扩增，通常高水平，每个肿瘤细胞的 EGFR 拷贝数超过 10-20（EGFR/着丝粒 7 比值>3）。EGFR 扩增与高 pT、pN 和预后不良相关（P=0.0004）。29 例原发肿瘤和 29 例匹配的淋巴结转移均发现相同的 EGFR 扩增状态。此外，对所有扩增的 BAC 和相应的淋巴结转移的三个至 16 个大切片进行 FISH 分析，并未发现 EGFR 扩增的任何异质性。未发现 EGFR 突变，但发现 1 个 KRAS 突变。
原发肿瘤和转移灶中 EGFR 扩增水平高且均一，提示抗 EGFR 药物在 BAC 中的潜在治疗应用。
