Stochastic Epigenetic Mutations Are Associated with Risk of Breast Cancer, Lung Cancer, and Mature B-cell Neoplasms
Stochastic Epigenetic Mutations Are Associated with Risk of Breast Cancer, Lung Cancer, and Mature B-cell Neoplasms
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DOI：
10.1158/1055-9965.epi-20-0451
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发表时间：
2020-10-01
影响因子：
3.8
通讯作者：
Fiorito, Giovanni
中科院分区：
文献类型：
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作者：
Gagliardi, Amedeo;Dugue, Pierre-Antoine;Fiorito, Giovanni
背景：与乳腺癌相关的表观遗传失调与包括癌症在内的几种疾病有关。随机表观遗传突变（SEM）的数量已被建议作为一个生物标志物的生命过程中积累的与糖尿病相关的DNA损伤;然而，SEMs在癌症中的预测作用很少被investigated.Methods：一个SEM，在一个给定的CpG位点，被定义为一个极端的离群值的DNA甲基化值分布在个人。我们在3个前瞻性队列的4,497个病例对照对中调查了SEM总数与8种癌症风险的关系。结果：在三项研究的荟萃分析中，经年龄和癌症危险因素校正后的Logistic回归模型估计的OR值为1.25，95%可信区间（CI）乳腺癌为1.11-1.41，乳腺癌为1.23;肺癌的95% CI为1.07-1.42。在墨尔本协作队列研究中，成熟B细胞肿瘤的OR为1.46; 95% CI，1.25-1.71。富集分析表明，SEM经常出现在沉默的基因组区域和转录因子结合位点由EZH 2和SUZ 12调节（分别为P < 0.0001和P = 0.0005）：多梳抑制复合物2（PCR 2）的两个组成部分。最后，我们发现，PCR 2特异性SEMs一般更稳定，随着时间的推移相比，SEMs发生在整个genome.Conclusions：SEMs的数量与不同的癌症在prediagnosis blood samples.Impact的风险较高：我们确定了一个候选的生物标志物癌症的早期检测，我们描述了一个致癌机制，涉及PCR 2复合蛋白值得进一步调查。
Background: Age-related epigenetic dysregulations are associated with several diseases, including cancer. The number of stochastic epigenetic mutations (SEM) has been suggested as a biomarker of life-course accumulation of exposure-related DNA damage; however, the predictive role of SEMs in cancer has seldom been investigated.Methods: A SEM, at a given CpG site, was defined as an extreme outlier of DNA methylation value distribution across individuals. We investigated the association of the total number of SEMs with the risk of eight cancers in 4,497 case-control pairs nested in three prospective cohorts. Furthermore, we investigated whether SEMs were randomly distributed across the genome or enriched in functional genomic regions.Results: In the three-study meta-analysis, the estimated ORs per one-unit increase in log(SEM) from logistic regression models adjusted for age and cancer risk factors were 1.25; 95% confidence interval (CI), 1.11-1.41 for breast cancer, and 1.23; 95% CI, 1.07-1.42 for lung cancer. In the Melbourne Collaborative Cohort Study, the OR for mature B-cell neoplasm was 1.46; 95% CI, 1.25-1.71. Enrichment analyses indicated that SEMs frequently occur in silenced genomic regions and in transcription factor binding sites regulated by EZH2 and SUZ12 (P < 0.0001 and P = 0.0005, respectively): two components of the polycomb repressive complex 2 (PCR2). Finally, we showed that PCR2-specific SEMs are generally more stable over time compared with SEMs occurring in the whole genome.Conclusions: The number of SEMs is associated with a higher risk of different cancers in prediagnostic blood samples.Impact: We identified a candidate biomarker for cancer early detection, and we described a carcinogenesis mechanism involving PCR2 complex proteins worthy of further investigations.