Department of Epidemiology, Biostatistics, and Biodemography, Institute of Public Health, University of Southern Denmark, Odense, Denmark; Danish Twin Registry, Institute of Public Health, University of Southern Denmark, Odense, Denmark.
Department of Haematology, Odense University Hospital, Odense, Denmark; Department of Clinical Research, University of Southern Denmark, Odense, Denmark.
Acta Oncol. 2024 Sep 18;63:710-717. doi: 10.2340/1651-226X.2024.40700.
This article aims to identify epigenetic markers and detect early development of hematopoietic malignancies through an epigenome wide association study of DNA methylation data.
This register-based study includes 1,085 Danish twins with 31 hematopoietic malignancies and methylation levels from 450,154 5'-C-phospate-G-3' (CpG) sites. Associations between methylation levels and incidence of hematopoietic malignancy is studied through time-to-event regression. The matched case-cotwin design, where one twin has a malignancy and the cotwin does not, is applied to enhance control for unmeasured shared confounding and false discoveries. Predictive performance is validated in the independent Older Finnish Twin Cohort.
We identified 67 epigenetic markers for hematopoietic malignancies of which 12 are linked to genes associated with hematologic malignancies. For some markers, we discovered a 2-3-fold relative risk difference for high versus low methylation. The identification of these 67 sites enabled the formation of a predictor demonstrating a cross-validated time-varying area under the curve (AUC) of 92% 3 years after individual blood sampling and persistent performance above 70% up to 6 years after blood sampling. This predictive performance was to a large extent recovered in the validation sample showing an overall Harrell's C of 73%. In conclusion, from a large population representative twin study on hematopoietic cancers, novel epigenetic markers were identified that may prove useful for early diagnosis.
本研究旨在通过对 DNA 甲基化数据进行全基因组关联研究，鉴定表观遗传标记并检测造血恶性肿瘤的早期发展。
本基于登记的研究纳入了 1085 名丹麦双胞胎，其中 31 名患有造血恶性肿瘤，其甲基化水平来自 450154 个 5'-C-磷酸鸟嘌呤-3'（CpG）位点。通过时间事件回归研究甲基化水平与造血恶性肿瘤发病之间的相关性。采用匹配的病例-同卵双胞胎设计，其中一个双胞胎患有恶性肿瘤，而另一个双胞胎没有，以增强对未测量的共同混杂因素和假发现的控制。在独立的老年芬兰双胞胎队列中验证了预测性能。
我们确定了 67 个与造血恶性肿瘤相关的表观遗传标记，其中 12 个与血液恶性肿瘤相关的基因有关。对于一些标记，我们发现高甲基化与低甲基化相比，风险差异增加了 2-3 倍。这些 67 个位点的鉴定使我们能够形成一个预测器，该预测器在个体采血后 3 年的时间变化曲线下面积（AUC）的交叉验证为 92%，并在采血后 6 年以上保持了 70%以上的性能。这种预测性能在验证样本中得到了很大程度的恢复，整体哈雷尔 C 值为 73%。总之，从一项针对造血癌症的大型代表性双胞胎研究中，发现了新的表观遗传标记，这些标记可能对早期诊断有用。
