Fallik David, Borrini Francesco, Boige Valérie, Viguier Jérôme, Jacob Sandrine, Miquel Catherine, Sabourin Jean-Christophe, Ducreux Michel, Praz Françoise
Department of Medicine, Institut Gustave Roussy, Centre National de la Recherche Scientifique Unité Mixte de Recherche 1598, Villejuif, France.
Cancer Res. 2003 Sep 15;63(18):5738-44.
The aim of our study was to assess the relationship between colorectal tumor responsiveness to irinotecan and microsatellite instability (MSI), a feature of colorectal tumors with DNA mismatch repair defect. Seventy-two patients with metastatic colorectal cancer were included in our retrospective study. A complete response to irinotecan was observed in 1 patient and a partial response in 10 patients, whereas 61 patients did not respond to this treatment. We analyzed the protein expression of hMLH1, hMSH2, and BAX by immunohistochemistry, determined the MSI phenotype, and looked for mutations in the coding repeats located in the transforming growth factor beta-RII, BAX, hMSH3, and hMSH6 genes. All 44 tumors analyzed expressed detectable levels of hMLH1; 1 tumor lacked hMSH2 staining, whereas 4 tumors showed a marked decrease in BAX expression. A better response to irinotecan was observed in the patients whose tumors have lost BAX expression (P < 0.001). Among the 7 tumors that displayed a MSI-H phenotype, 4 responded to irinotecan, whereas only 7 of the 65 MSI-L/ microsatellite stable tumors did (P = 0.009). Seven of the 72 tumors had inactivating mutations in the coding repeats of the target genes. Three tumors displayed a mutation in the poly-A10 tract of the transforming growth factor beta-RII gene, associated with a 1-bp deletion in the poly-A8 tract of hMSH3 in one tumor and with a 1-bp deletion in the poly-G8 tract of BAX in another. Four tumors displayed mutations in the poly-G8 repeat of BAX, whereas 2 mutations in hMSH6 and hMSH3 were characterized. Among the 7 tumors with mutations in these target genes, 5 responded to irinotecan, whereas only 6 of the other 65 tumors did (P < 0.001), indicating that MSI-driven inactivation of target genes modifies tumor chemosensitivity. Our observations allowed us to define the first useful predictive criteria for irinotecan response in patients with colorectal cancer.
我们研究的目的是评估结直肠癌对伊立替康的反应性与微卫星不稳定性（MSI）之间的关系，MSI是具有DNA错配修复缺陷的结直肠癌的一个特征。72例转移性结直肠癌患者纳入我们的回顾性研究。1例患者对伊立替康完全缓解，10例部分缓解，而61例患者对该治疗无反应。我们通过免疫组化分析hMLH1、hMSH2和BAX的蛋白表达，确定MSI表型，并寻找转化生长因子β-RII、BAX、hMSH3和hMSH6基因编码重复序列中的突变。分析的所有44个肿瘤均表达可检测水平的hMLH1；1个肿瘤缺乏hMSH2染色，而4个肿瘤显示BAX表达明显降低。肿瘤失去BAX表达的患者对伊立替康反应更好（P < 0.001）。在7个显示MSI-H表型的肿瘤中，4个对伊立替康有反应，而65个MSI-L/微卫星稳定肿瘤中只有7个有反应（P = 0.009）。72个肿瘤中有7个在靶基因的编码重复序列中有失活突变。3个肿瘤在转化生长因子β-RII基因的多聚A10区域有突变，其中1个肿瘤与hMSH3的多聚A8区域1个碱基缺失相关，另1个肿瘤与BAX的多聚G8区域1个碱基缺失相关。4个肿瘤在BAX的多聚G8重复序列中有突变，而hMSH6和hMSH3中有2个突变被鉴定。在这7个靶基因突变的肿瘤中，5个对伊立替康有反应，而其他65个肿瘤中只有6个有反应（P < 0.001），表明MSI驱动的靶基因失活改变了肿瘤的化学敏感性。我们的观察结果使我们能够为结直肠癌患者伊立替康反应定义首个有用的预测标准。
