Survival in stage II/III colorectal cancer is independently predicted by chromosomal and microsatellite instability, but not by specific driver mutations
Survival in stage II/III colorectal cancer is independently predicted by chromosomal and microsatellite instability, but not by specific driver mutations
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DOI：
10.1038/ajg.2013.292
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发表时间：
2013-11-01
影响因子：
9.8
通讯作者：
Sieber, Oliver M.
中科院分区：
文献类型：
--
作者：
Mouradov, Dmitri;Domingo, Enric;Sieber, Oliver M.
目的：微卫星不稳定性（MSI）是结直肠癌（CRC）良好预后的既定标志。染色体不稳定性 (CIN) 与 MSI 呈强烈负相关，并且在少数研究中已被证明是预后不良的标志。然而，存在大量“双阴性”(MSI-/CIN-) CRC。这些患者的预后尚不清楚。此外，MSI 和 CIN 均与特定的分子变化相关，例如与预后相关的 KRAS 和 BRAF 突变。目前尚不清楚 MSI、CIN 和特定基因突变中哪一个是生存的主要预测因素。 方法：我们评估了 VICTOR 试验中 822 名患者的 CIN、MSI、KRAS、NRAS、BRAF、PIK3CA、FBXW7 和 TP53 突变以及染色体 18q 杂合性缺失 (LOH) 的预后价值（无病生存，DFS） II/III期CRC。我们对澳大利亚社区队列 (N=375) 中的有希望的关联进行了跟踪。结果：在 VICTOR 患者中，没有特定突变与 DFS 相关，但在调整分期、年龄、性别、肿瘤位置和治疗后，单独的 MSI 和 CIN 显示出显着关联。 VICTOR 和社区队列的综合分析显示，MSI 和 CIN 是 DFS 的独立预测因子（对于 MSI，风险比 (HR)=0.58，95% 置信区间 (CI) 0.36-0.93，P=0.021；对于 CIN，HR=1.54，95% CI 1.14-2.08，P=0.005）和联合 CIN/MSI 测试显着改善了单独 MSI 的预后预测（P=0.028）。较高水平的 CIN 与逐渐较差的 DFS 单调相关，并且 CIN 的半定量测量比简单的 CIN+/- 变量是更好的结果预测指标。 CIN 的所有测量值都比最近描述的 Watanabe LOH 比率更好地预测 DFS。 结论：MSI 和 CIN 是 II/III 期 CRC 的 DFS 的独立预测因子。 CRC 复发的预后分子检测目前应使用 MSI 和 CIN 的定量测量，而不是特定的基因突变。
OBJECTIVES: Microsatellite instability (MSI) is an established marker of good prognosis in colorectal cancer (CRC). Chromosomal instability (CIN) is strongly negatively associated with MSI and has been shown to be a marker of poor prognosis in a small number of studies. However, a substantial group of "double-negative" (MSI-/CIN-) CRCs exists. The prognosis of these patients is unclear. Furthermore, MSI and CIN are each associated with specific molecular changes, such as mutations in KRAS and BRAF, that have been associated with prognosis. It is not known which of MSI, CIN, and the specific gene mutations are primary predictors of survival.METHODS: We evaluated the prognostic value (disease-free survival, DFS) of CIN, MSI, mutations in KRAS, NRAS, BRAF, PIK3CA, FBXW7, and TP53, and chromosome 18q loss-of-heterozygosity (LOH) in 822 patients from the VICTOR trial of stage II/III CRC. We followed up promising associations in an Australian community-based cohort (N=375).RESULTS: In the VICTOR patients, no specific mutation was associated with DFS, but individually MSI and CIN showed significant associations after adjusting for stage, age, gender, tumor location, and therapy. A combined analysis of the VICTOR and community-based cohorts showed that MSI and CIN were independent predictors of DFS (for MSI, hazard ratio (HR)=0.58, 95% confidence interval (CI) 0.36-0.93, and P=0.021; for CIN, HR=1.54, 95% CI 1.14-2.08, and P=0.005), and joint CIN/MSI testing significantly improved the prognostic prediction of MSI alone (P=0.028). Higher levels of CIN were monotonically associated with progressively poorer DFS, and a semi-quantitative measure of CIN was a better predictor of outcome than a simple CIN+/- variable. All measures of CIN predicted DFS better than the recently described Watanabe LOH ratio.CONCLUSIONS: MSI and CIN are independent predictors of DFS for stage II/III CRC. Prognostic molecular tests for CRC relapse should currently use MSI and a quantitative measure of CIN rather than specific gene mutations.