Abstract
BackgroundEpigenetic alterations may contribute to early detection of cancer. We evaluated the association of blood DNA methylation with lymphatic–hematopoietic cancers and, for comparison, with solid cancers. We also evaluated the predictive ability of DNA methylation for lymphatic–hematopoietic cancers.MethodsBlood DNA methylation was measured using the Illumina Infinium methylationEPIC array in 2324 Strong Heart Study participants (41.4% men, mean age 56 years). 788,368 CpG sites were available for differential DNA methylation analysis for lymphatic–hematopoietic, solid and overall cancers using elastic-net and Cox regression models. We conducted replication in an independent population: the Framingham Heart Study. We also analyzed differential variability and conducted bioinformatic analyses to assess for potential biological mechanisms.ResultsOver a follow-up of up to 28 years (mean 15), we identified 41 lymphatic–hematopoietic and 394 solid cancer cases. A total of 126 CpGs for lymphatic–hematopoietic cancers, 396 for solid cancers, and 414 for overall cancers were selected as predictors by the elastic-net model. For lymphatic–hematopoietic cancers, the predictive ability (C index) increased from 0.58 to 0.87 when adding these 126 CpGs to the risk factor model in the discovery set. The association was replicated with hazard ratios in the same direction in 28 CpGs in the Framingham Heart Study. When considering the association of variability, rather than mean differences, we found 432 differentially variable regions for lymphatic–hematopoietic cancers.ConclusionsThis study suggests that differential methylation and differential variability in blood DNA methylation are associated with lymphatic–hematopoietic cancer risk. DNA methylation data may contribute to early detection of lymphatic–hematopoietic cancers.
Highlights
Epigenetic modifications—heritable and reversible changes in the genome without changes in the DNA sequence—are involved in tumorigenesis, potentially enabling early cancer detection
We ran elastic-net in the Strong Heart Study (SHS) restricting the Cytosine–guanine dinucleotide (CpG) to those present in 450 K and we fitted an elastic-net model in the Framingham Heart Study (FHS) population introducing the CpGs that the model selected in the SHS
We found 432 Differentially variable region (DVR) for lymphatic–hematopoietic cancers (Table 8 shows top 15); 78 were Differentially methylated region (DMR) as well
Summary
Epigenetic modifications—heritable and reversible changes in the genome without changes in the DNA sequence—are involved in tumorigenesis, potentially enabling early cancer detection. Modifications in DNA methylation, the most established epigenetic measure, occur in early stages of tumor development [1] and have been associated with cancer-related biological processes including oxidative stress [2] and apoptosis [3]. DNA methylation-based biomarkers have been a target for early detection of cancer [5] due to their early and frequent emergence in tumors, their high quality measurement by well-established methods, their stability over time, their presence in different body fluids, and their cell type specificity [6]. Lymphatic and hematopoietic cancers affect the blood, bone marrow, lymph, and lymphatic system tissues. They are classified as myeloid (affecting mainly blood, including leukemia) and lymphoid (affecting mainly lymph nodes) neoplasms [7]. We evaluated the predictive ability of DNA methylation for lymphatic–hematopoietic cancers
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