Division of Molecular Epidemiology, Jikei University School of Medicine, 3-25-8 Nishi-shimbashi, Minato-ku, Tokyo 105-8461, Japan.
Clin Exp Metastasis. 2012 Jan;29(1):19-25. doi: 10.1007/s10585-011-9425-5. Epub 2011 Sep 28.
Tumors with certain mutations in the epidermal growth factor receptor (EGFR) family genes dramatically respond to EGFR inhibitors. Therefore, these mutations are important factors that influence disease progression and patient survival. We previously studied the mutation status of EGFR in patients with head and neck squamous cell carcinoma (HNSCC). However, the mutation status of lymph node metastases and the frequency of mutations in EGFR family genes have not been extensively studied. In this study, we sequenced the catalytic domains of the three other members of the EGFR family, HER2, HER3, and HER4 in 92 clinical samples of HNSCC. We identified a HER2 mutation (K716E) in one sample but no mutations were found in HER3 or HER4. Next to investigate the relationship between EGFR mutations and tumor metastasis, we compared the DNA sequences of the EGFR gene between the primary tumor and the lymph node metastasis in 31 clinical samples. Only one of the patients with an EGFR mutation in the primary HNSCC carried the same mutation (L858R) in the lymph node metastasis. Finally, we explored the tumorigenic potential of the EGFR mutations that we had previously identified and their sensitivity to two different EGFR tyrosine kinase inhibitors (CL-387785, OSI-420). Ba/F3 cells transformed with mutant EGFR genes were sensitive to treatment with lower concentrations of CL-387785 than of OSI-420. These results contribute to our understanding of the genetic basis of drug sensitivity and will help design drugs that specifically target different subtypes of HNSCC.
具有表皮生长因子受体（EGFR）家族基因突变的肿瘤对 EGFR 抑制剂有显著反应。因此，这些突变是影响疾病进展和患者生存的重要因素。我们之前研究了头颈部鳞状细胞癌（HNSCC）患者中 EGFR 的突变状态。然而，淋巴结转移的突变状态和 EGFR 家族基因的突变频率尚未得到广泛研究。在这项研究中，我们对 92 例 HNSCC 临床样本中的 EGFR 家族的另外三个成员 HER2、HER3 和 HER4 的催化结构域进行了测序。我们在一个样本中鉴定出一个 HER2 突变（K716E），但在 HER3 或 HER4 中未发现突变。接下来为了研究 EGFR 突变与肿瘤转移之间的关系，我们比较了 31 例临床样本中原发性肿瘤和淋巴结转移之间的 EGFR 基因的 DNA 序列。只有一名原发性 HNSCC 中 EGFR 突变的患者在淋巴结转移中携带相同的突变（L858R）。最后，我们探讨了我们之前鉴定的 EGFR 突变的肿瘤发生潜力及其对两种不同的 EGFR 酪氨酸激酶抑制剂（CL-387785、OSI-420）的敏感性。用突变 EGFR 基因转化的 Ba/F3 细胞对较低浓度的 CL-387785 比 OSI-420 更敏感。这些结果有助于我们了解药物敏感性的遗传基础，并将有助于设计针对不同亚型的 HNSCC 的靶向药物。
