A Cohort Study of Tumoral LINE-1 Hypomethylation and Prognosis in Colon Cancer
A Cohort Study of Tumoral LINE-1 Hypomethylation and Prognosis in Colon Cancer
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DOI：
10.1093/jnci/djn359
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发表时间：
2008-12-03
期刊：
影响因子：
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通讯作者：
Fuchs, Charles S.
中科院分区：
文献类型：
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作者：
Ogino, Shuji;Nosho, Katsuhiko;Fuchs, Charles S.
全基因组DNA低甲基化在基因组不稳定和结直肠癌发生中起重要作用。然而，细胞DNA甲基化水平和患者预后之间的关系仍然不确定。使用两个独立的前瞻性队列中的643例结肠癌，我们使用焦磷酸测序技术对重复的长散布核苷酸元件-1(LINE-1)元件中的DNA甲基化进行了定量，这是一个很好的全球DNA甲基化水平的指标。我们使用COX比例风险模型计算结肠癌特异性和总体死亡率的风险比(HR)，调整患者和肿瘤特征，包括CpG岛甲基化表型(CIMP)。统计检验是两面性的。LINE-1低甲基化与结肠癌特异性死亡率(多变量HR=2.37，95%可信区间[CI]=1.42至3.94；P(趋势)和0.001)和总体死亡率(多变量HR=1.85，95%CI=1.25至2.75；P(趋势)=0.002)的统计学显著相关。包括性别、年龄、肿瘤位置、分期、CIMP、微卫星不稳定、KRAS、BRAF、P53和染色体不稳定状态在内的两个独立的临床和分子特征的队列和层级之间的关联是一致的。总之，在结肠癌患者中，肿瘤LINE-1低甲基化独立地与较短的生存期相关。
Genome-wide DNA hypomethylation plays has an important role in genomic instability and colorectal carcinogenesis. However, the relationship between cellular DNA methylation level and patient outcome remains uncertain. Using 643 colon cancers in two independent prospective cohorts, we quantified DNA methylation in repetitive long interspersed nucleotide element-1 (LINE-1) elements using pyrosequencing, which is a good indicator of global DNA methylation level. We used Cox proportional hazard models to calculate hazard ratios (HRs) of colon cancer-specific and overall mortality, adjusting for patient and tumoral features, including CpG island methylator phenotype (CIMP). Statistical tests were two-sided. LINE-1 hypomethylation was linearly associated with a statistically significant increase in colon cancer-specific mortality (for a 30% decrease in LINE-1 methylation: multivariable HR = 2.37, 95% confidence interval [CI] = 1.42 to 3.94; P(trend) < .001) and overall mortality (multivariable HR = 1.85, 95% CI = 1.25 to 2.75; P(trend) = .002). The association was consistent across the two independent cohorts and strata of clinical and molecular characteristics, including sex, age, tumor location, stage, and CIMP, microsatellite instability, KRAS, BRAF, p53, and chromosomal instability status. In conclusion, tumoral LINE-1 hypomethylation is independently associated with shorter survival among colon cancer patients.