CpG island methylator phenotype, microsatellite instability, BRAF mutation and clinical outcome in colon cancer.
CpG island methylator phenotype, microsatellite instability, BRAF mutation and clinical outcome in colon cancer.
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DOI：
10.1136/gut.2008.155473
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发表时间：
2009-01
期刊：
影响因子：
24.5
通讯作者：
Fuchs CS
中科院分区：
文献类型：
--
作者：
Ogino S;Nosho K;Kirkner GJ;Kawasaki T;Meyerhardt JA;Loda M;Giovannucci EL;Fuchs CS
以广泛启动子甲基化为特征的CpG岛甲基化表型（CIMP）与结直肠癌中的微卫星不稳定性（MSI）和BRAF突变相关。CIMP、MSI和BRAF突变对患者结局的独立影响仍不确定。在两项独立的队列研究中，利用649例结肠癌（I-IV期），我们通过MethyLight定量了8种CIMP特异性启动子[CACNA 1G、CDKN 2A（p16）、CRABP 1、IGF 2、MLH 1、NEUROG 1、RUNX 3和SOCS 1]以及MINT 1、MINT 31、p14、MGMT 1、IGFBP 3、MGMT和WRN中的DNA甲基化。我们检查了MSI、KRAS和BRAF状态。考克斯比例风险模型计算了结肠癌特异性死亡率和总体死亡率的风险比（HR），调整了患者特征和肿瘤分子特征。在调整患者生存的其他预测因素后，CIMP高水平癌症患者[126例（19%）肿瘤具有≥6/8甲基化CIMP特异性启动子]的结肠癌特异性死亡率显著较低[多变量HR 0.44，95%置信区间（CI）0.22-0.88]，而BRAF突变与高癌症特异性死亡率显著相关（多变量HR 1.97，95%CI，1.13-3.42）。在MSI高的肿瘤中观察到癌症特异性死亡率降低的趋势（多变量HR 0.70，95% CI，0.36-1.37）。在分层分析中，CIMP高的肿瘤与结肠癌特异性死亡率的显著降低相关，无论MSI和BRAF状态如何。CIMP高和低死亡率之间的关系似乎在所有阶段都是一致的。KRAS突变与患者结局无关。CIMP高似乎是结肠癌特异性死亡率低的独立预测因子，而BRAF突变与结肠癌特异性死亡率高相关。
The CpG island methylator phenotype (CIMP) characterized by widespread promoter methylation is associated with microsatellite instability (MSI) and BRAF mutation in colorectal cancer. The independent effect of CIMP, MSI and BRAF mutation on patient outcome remains uncertain. Utilizing 649 colon cancers (stage I–IV) in two independent cohort studies, we quantified DNA methylation in 8 CIMP-specific promoters [CACNA1G, CDKN2A (p16), CRABP1, IGF2, MLH1, NEUROG1, RUNX3, and SOCS1], as well as MINT1, MINT31, p14, HIC1, IGFBP3, MGMT and WRN by MethyLight. We examined MSI, KRAS and BRAF status. Cox proportional hazard models computed hazard ratios (HRs) for colon cancer-specific and overall mortalities, adjusting for patient characteristics and tumoral molecular features. After adjustment for other predictors of patient survival, patients with CIMP-high cancers [126 (19%) tumors with ≥6/8 methylated CIMP-specific promoters] experienced a significantly low colon cancer-specific mortality [multivariate HR 0.44, 95% confidence interval (CI) 0.22–0.88], whereas BRAF mutation was significantly associated with a high cancer-specific mortality (multivariate HR 1.97, 95% CI, 1.13–3.42). A trend toward a low cancer-specific mortality was observed for MSI-high tumors (multivariate HR 0.70, 95% CI, 0.36–1.37). In stratified analyses, CIMP-high tumors were associated with a significant reduction in colon cancer-specific mortality, regardless of both MSI and BRAF status. The relation between CIMP-high and lower mortality appeared to be consistent across all stages. KRAS mutation was unrelated to patient outcome. CIMP-high appears to be an independent predictor of a low colon cancer-specific mortality, while BRAF mutation is associated with a high colon cancer-specific mortality.
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影响因子：
24.5
作者：
Lees, N. P.;Harrison, K. L.;Povey, A. C.
通讯作者：
Povey, A. C.
影响因子：
24.5
作者：
Ogino, Shuji;Kawasaki, Takako;Fuchs, Charles S.
通讯作者：
Fuchs, Charles S.
影响因子：
24.5
作者：
Ogino, S.;Cantor, M.;Fuchs, C. S.
通讯作者：
Fuchs, C. S.
影响因子：
7.5
作者：
Kawasaki, Takako;Ohnishi, Mutsuko;Ogino, Shuji
通讯作者：
Ogino, Shuji
影响因子：
78.5
作者：
Issa, JP
通讯作者：
Issa, JP