Division of Cancer Epidemiology and Genetics (DCEG); U.S. National Cancer Institute (NCI); National Institutes of Health (NIH); Department of Health and Human Services (DHHS); Bethesda, MD USA.
Department of Chronic Disease Prevention; National Institute for Health and Welfare; Helsinki, Finland.
Epigenetics. 2014 Mar;9(3):404-15. doi: 10.4161/epi.27386. Epub 2013 Dec 6.
Global methylation in blood DNA has been associated with bladder cancer risk in case-control studies, but has not been examined prospectively. We examined the association between LINE1 total percent 5-methylcytosine and bladder cancer risk using pre-diagnostic blood DNA from the United States-based, Prostate, Lung, Colorectal, Ovarian Cancer Screening Trial (PLCO) (299 cases/676 controls), and the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) cohort of Finnish male smokers (391 cases/778 controls). Logistic regression adjusted for age at blood draw, study center, pack-years of smoking, and sex was used to estimate odd ratios (ORs) and 95% confidence intervals (CIs) using study- and sex-specific methylation quartiles. In PLCO, higher, although non-significant, bladder cancer risks were observed for participants in the highest three quartiles (Q2-Q4) compared with the lowest quartile (Q1) (OR = 1.36, 95% CI: 0.96 -1.92). The association was stronger in males (Q2-Q4 vs. Q1 OR = 1.48, 95% CI: 1.00-2.20) and statistically significant among male smokers (Q2-Q4 vs. Q1 OR = 1.83, 95% CI: 1.14-2.95). No association was found among females or female smokers. Findings for male smokers were validated in ATBC (Q2-Q4 vs. Q1: OR = 2.31, 95% CI: 1.62-3.30) and a highly significant trend was observed (P = 8.7 × 10(-7)). After determining that study data could be combined, pooled analysis of PLCO and ATBC male smokers (580 cases/1119 controls), ORs were significantly higher in Q2-Q4 compared with Q1 (OR = 2.03, 95% CI: 1.52-2.72), and a trend across quartiles was observed (P = 0.0001). These findings suggest that higher global methylation levels prior to diagnosis may increase bladder cancer risk, particularly among male smokers.
血液 DNA 中的全球甲基化与病例对照研究中的膀胱癌风险相关，但尚未进行前瞻性研究。我们使用来自美国前列腺、肺、结直肠、卵巢癌筛查试验 (PLCO) 的预诊断血液 DNA（299 例/676 例对照）和芬兰男性吸烟者的α-生育酚、β-胡萝卜素癌症预防 (ATBC) 队列（391 例/778 例对照），检查了 LINE1 总 5-甲基胞嘧啶百分比与膀胱癌风险之间的关联。使用研究和性别特异性甲基化四分位值，通过血液采集时的年龄、研究中心、吸烟包年数和性别进行逻辑回归调整，以估计比值比 (OR) 和 95%置信区间 (CI)。在 PLCO 中，与最低四分位组 (Q1) 相比，最高三个四分位组 (Q2-Q4) 的参与者膀胱癌风险虽然无统计学意义，但仍较高（OR=1.36，95%CI：0.96-1.92）。这种关联在男性中更强（Q2-Q4 与 Q1 的 OR=1.48，95%CI：1.00-2.20），并且在男性吸烟者中具有统计学意义（Q2-Q4 与 Q1 的 OR=1.83，95%CI：1.14-2.95）。在女性或女性吸烟者中未发现关联。男性吸烟者的发现在 ATBC 中得到验证（Q2-Q4 与 Q1：OR=2.31，95%CI：1.62-3.30），并且观察到非常显著的趋势（P=8.7×10(-7)）。在确定可以合并研究数据后，对 PLCO 和 ATBC 男性吸烟者（580 例/1119 例对照）进行汇总分析，Q2-Q4 与 Q1 相比，OR 明显更高（OR=2.03，95%CI：1.52-2.72），并且观察到四分位组的趋势（P=0.0001）。这些发现表明，在诊断前更高的全球甲基化水平可能会增加膀胱癌风险，尤其是在男性吸烟者中。
