Reduced likelihood of metastases in patients with microsatellite-unstable colorectal cancer
Reduced likelihood of metastases in patients with microsatellite-unstable colorectal cancer
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DOI：
10.1158/1078-0432.ccr-07-0366
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发表时间：
2007-07-01
影响因子：
11.5
通讯作者：
Santoro, Armando
中科院分区：
文献类型：
--
作者：
Malesci, Alberto;Laghi, Luigi;Santoro, Armando
目的：结直肠癌患者出现高频微卫星不稳定性（MSI）时预后较好。虽然与早期肿瘤相关，但MSI已被认为是生存的独立预测因子。在过去十年中，我们测试了MSI在大量结直肠癌患者中的预后价值。实验设计：分析893例以微卫星状态为特征的连续结直肠癌患者的生存情况。89例（10%）MSI癌患者根据肿瘤错配修复（tumor mismatch repair， MMR）缺陷、MMR种系突变、hMLH1和p16启动子甲基化、BRAF和K-ras突变、靶基因移帧进行分类。结果：MSI肿瘤患者的结直肠癌特异性生存率显著高于稳定肿瘤（MSS）患者（P = 0.02）。如果将肿瘤分期纳入多变量分析，MSI并不能预测癌症相关死亡风险的显著降低[危险比，0.72；95%置信区间（95% CI）， 0.40-1.29；P = 0.27]。相反，MSI与诊断时淋巴结转移（优势比为0.31,95% CI为0.17-0.56,P < 0.001）和远端器官转移（优势比为0.13,95% CI为0.05-0.33,P < 0.001）的可能性降低密切相关，而与肿瘤病理特征无关。转移风险降低和预后良好的分子预测因子包括：所有MSI肿瘤的TGF β RII突变，遗传性非息肉病性结直肠癌的hMSH2缺乏，散发性hmlh1缺陷癌症的p16甲基化缺失。结论：肿瘤MSI是结直肠癌患者生存期依赖的预测因子。MSI癌症患者转移的可能性降低与原发肿瘤的特定遗传和表观遗传改变有关。
Purpose: The outcome of patients with colorectal cancer is more favorable when the tumor exhibits high-frequency microsatellite instability (MSI). Although associated with earlier-stage tumors, MSI has been proposed as an independent predictor of survival. We tested the prognostic value of MSI in a large series of patients diagnosed with colorectal cancer in the last decade.Experimental Design: The survival of 893 consecutive patients with colorectal cancer characterized by microsatellite status was analyzed. The 89 (10%) patients with MSI cancer were classified according to tumor mismatch repair (MMR) defect, MMR germ-line mutation, hMLH1 and p16 promoter methylation, BRAF and K-ras mutations, and frameshifts of target genes.Results: The colorectal cancer-specific survival was significantly (P = 0.02) better in patients with MSI cancer than in those with stable tumor (MSS). MSI did not predict a significantly lower risk of cancer-related death if tumor stage was included in the multivariate analysis [hazard ratio, 0.72; 95% confidence interval (95% CI), 0.40-1.29; P = 0.27]. Instead, MSI was strongly associated with a decreased likelihood of lymph node (odds ratio, 0.31; 95% CI, 0.17-0.56; P < 0.001) and distant organ (odds ratio, 0.13; 95% CI, 0.05-0.33; P < 0.001) metastases at diagnosis, independently of tumor pathologic features. Molecular predictors of reduced metastatic risk, and then of more favorable prognosis, included TGF beta RII mutation for all MSI tumors, hMSH2 deficiency for hereditary non-polyposis colorectal cancer, and absence of p16 methylation for sporadic hMLH1-deficient cancers.Conclusions: Tumor MSI is a stage-dependent predictor of survival in patients with colorectal cancer. The decreased likelihood of metastases in patients with MSI cancer is associated with specific genetic and epigenetic changes of the primary tumor.