Center for Population Epigenetics, Robert H. Lurie Comprehensive Cancer Center and Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
Division of Biostatistics, Washington University in St. Louis, St. Louis, Missouri.
Cancer Prev Res (Phila). 2018 Aug;11(8):511-522. doi: 10.1158/1940-6207.CAPR-17-0413. Epub 2018 Jun 12.
Researchers hypothesized that telomere shortening facilitates carcinogenesis. Previous studies found inconsistent associations between blood leukocyte telomere length (LTL) and cancer. Epigenetic reprogramming of telomere maintenance mechanisms may help explain this inconsistency. We examined associations between DNA methylation in telomere-related genes (TRG) and cancer. We analyzed 475 participants providing 889 samples 1 to 3 times (median follow-up, 10.1 years) from 1999 to 2013 in the Normative Aging Study. All participants were cancer-free at each visit and blood leukocytes profiled using the Illumina 450K array. Of 121 participants who developed cancer, 34 had prostate cancer, 10 melanoma, 34 unknown skin malignancies, and 43 another cancer. We examined 2,651 CpGs from 80 TRGs and applied a combination of Cox and mixed models to identify CpGs prospectively associated with cancer (at FDR < 0.05). We also explored trajectories of DNA methylation, logistic regression stratified by time to diagnosis/censoring, and cross-sectional models of LTL at first blood draw. We identified 30 CpGs on 23 TRGs whose methylation was positively associated with cancer incidence (β = 1.0-6.93) and one protective CpG in (β = -0.65) of which 87% were located in TRG promoters. Methylation trajectories of 21 CpGs increased in cancer cases relative to controls; at 4 to 8 years prediagnosis/censoring, 17 CpGs were positively associated with cancer. Three CpGs were cross-sectionally associated with LTL. TRG methylation may be a mechanism through which LTL dynamics reflect cancer risk. Future research should confirm these findings and explore potential mechanisms underlying these findings, including telomere maintenance and DNA repair dysfunction. .
研究人员假设端粒缩短促进了致癌作用。先前的研究发现，血液白细胞端粒长度（LTL）与癌症之间的关联不一致。端粒维持机制的表观遗传重编程可能有助于解释这种不一致。我们研究了端粒相关基因（TRG）中的 DNA 甲基化与癌症之间的关联。我们分析了 1999 年至 2013 年期间在正常衰老研究中提供 889 次样本（中位随访时间为 10.1 年）的 475 名参与者的数据。每次就诊时所有参与者均无癌症，并且使用 Illumina 450K 阵列对血液白细胞进行了分析。在 121 名发生癌症的参与者中，34 名患有前列腺癌，10 名患有黑色素瘤，34 名患有未知皮肤恶性肿瘤，43 名患有其他癌症。我们检查了 80 个 TRG 中的 2651 个 CpG，并应用 Cox 和混合模型的组合来确定与癌症（在 FDR < 0.05 时）具有前瞻性关联的 CpG。我们还探索了 DNA 甲基化的轨迹，按诊断/截止时间分层的逻辑回归以及首次采血时的 LTL 横截面模型。我们确定了 23 个 TRG 上的 30 个 CpG，其甲基化与癌症发病率呈正相关（β = 1.0-6.93），而在一个保护性 CpG 中（β = -0.65），其中 87％位于 TRG 启动子中。与对照组相比，癌症病例中 21 个 CpG 的甲基化轨迹增加；在诊断/截止前 4 至 8 年，有 17 个 CpG 与癌症呈正相关。三个 CpG 与 LTL 横截面相关。TRG 甲基化可能是 LTL 动态反映癌症风险的一种机制。未来的研究应证实这些发现，并探索这些发现背后的潜在机制，包括端粒维持和 DNA 修复功能障碍。
