Background: Self-reported information may not accurately capture smoking exposure. We aimed to evaluate whether smoking-associated DNA methylation markers improve urothelial cell carcinoma (UCC) risk prediction. Methods: Conditional logistic regression was used to assess associations between blood-based methylation and UCC risk using two matched case–control samples: 404 pairs from the Melbourne Collaborative Cohort Study (MCCS) and 440 pairs from the Women's Health Initiative (WHI) cohort. Results were pooled using fixed-effects meta-analysis. We developed methylation-based predictors of UCC and evaluated their prediction accuracy on two replication data sets using the area under the curve (AUC). Results: The meta-analysis identified associations ( P < 4.7 × 10−5) for 29 of 1,061 smoking-associated methylation sites, but these were substantially attenuated after adjustment for self-reported smoking. Nominally significant associations ( P < 0.05) were found for 387 (36%) and 86 (8%) of smoking-associated markers without/with adjustment for self-reported smoking, respectively, with same direction of association as with smoking for 387 (100%) and 79 (92%) markers. A Lasso-based predictor was associated with UCC risk in one replication data set in MCCS [ N = 134; odds ratio per SD (OR) = 1.37; 95% CI, 1.00–1.90] after confounder adjustment; AUC = 0.66, compared with AUC = 0.64 without methylation information. Limited evidence of replication was found in the second testing data set in WHI ( N = 440; OR = 1.09; 95% CI, 0.91–1.30). Conclusions: Combination of smoking-associated methylation marks may provide some improvement to UCC risk prediction. Our findings need further evaluation using larger data sets. Impact: DNA methylation may be associated with UCC risk beyond traditional smoking assessment and could contribute to some improvements in stratification of UCC risk in the general population. This article is featured in Highlights of This Issue, [p. 2141][1] [1]: /lookup/volpage/30/2141?iss=12

中文翻译：

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用于预测尿路上皮癌风险的吸烟甲基化标记

背景：自我报告的信息可能无法准确捕捉吸烟暴露情况。我们旨在评估吸烟相关的 DNA 甲基化标志物是否能改善尿路上皮细胞癌 (UCC) 的风险预测。方法：条件逻辑回归用于评估血液甲基化与 UCC 风险之间的关联，使用两个匹配的病例对照样本：来自墨尔本协作队列研究 (MCCS) 的 404 对和来自女性健康倡议 (WHI) 队列的 440 对。使用固定效应荟萃分析汇总结果。我们开发了基于甲基化的 UCC 预测因子，并使用曲线下面积 (AUC) 在两个复制数据集上评估了它们的预测准确性。结果：荟萃分析确定了 1,061 个与吸烟相关的甲基化位点中的 29 个的关联（P < 4.7 × 10−5），但在对自我报告的吸烟进行调整后，这些都大大减少了。分别对 387 个（36%）和 86 个（8%）吸烟相关标志物进行了标称显着关联（P < 0.05），没有/没有对自我报告的吸烟进行调整，与 387 个吸烟相关的方向相同（ 100%) 和 79 (92%) 个标记。在 MCCS 的一个复制数据集中，基于 Lasso 的预测因子与 UCC 风险相关 [N = 134；每个标准差的优势比 (OR) = 1.37；95% CI, 1.00–1.90] 混杂调整后；AUC = 0.66，与没有甲基化信息的 AUC = 0.64 相比。在 WHI 的第二个测试数据集中发现了有限的复制证据（N = 440；OR = 1.09；95% CI，0.91-1.30）。结论：吸烟相关甲基化标记的组合可能为 UCC 风险预测提供一些改进。我们的发现需要使用更大的数据集进行进一步评估。影响：DNA 甲基化可能与传统吸烟评估之外的 UCC 风险相关，并可能有助于改善一般人群中 UCC 风险的分层。这篇文章被收录在本期的亮点中，[p. 2141][1][1]：/lookup/volpage/30/2141?iss=12