Abstract
BackgroundA key focus in cancer research is the discovery of biomarkers that accurately diagnose early lesions in non-invasive tissues. Several studies have identified malignancy-associated DNA methylation changes in blood, yet no general cancer biomarker has been identified to date. Here, we explore the potential of blood DNA methylation as a biomarker of pan-cancer (cancer of multiple different origins) in 41 female cancer discordant monozygotic (MZ) twin-pairs sampled before or after diagnosis using the Illumina HumanMethylation450 BeadChip.ResultsWe analysed epigenome-wide DNA methylation profiles in 41 cancer discordant MZ twin-pairs with affected individuals diagnosed with tumours at different single primary sites: the breast, cervix, colon, endometrium, thyroid gland, skin (melanoma), ovary, and pancreas. No significant global differences in whole blood DNA methylation profiles were observed. Epigenome-wide analyses identified one novel pan-cancer differentially methylated position at false discovery rate (FDR) threshold of 10 % (cg02444695, P = 1.8 × 10−7) in an intergenic region 70 kb upstream of the SASH1 tumour suppressor gene, and three suggestive signals in COL11A2, AXL, and LINC00340. Replication of the four top-ranked signals in an independent sample of nine cancer-discordant MZ twin-pairs showed a similar direction of association at COL11A2, AXL, and LINC00340, and significantly greater methylation discordance at AXL compared to 480 healthy concordant MZ twin-pairs. The effects at cg02444695 (near SASH1), COL11A2, and LINC00340 were the most promising in biomarker potential because the DNA methylation differences were found to pre-exist in samples obtained prior to diagnosis and were limited to a 5-year period before diagnosis. Gene expression follow-up at the top-ranked signals in 283 healthy individuals showed correlation between blood methylation and gene expression in lymphoblastoid cell lines at PRL, and in the skin tissue at AXL. A significant enrichment of differential DNA methylation was observed in enhancer regions (P = 0.03).ConclusionsWe identified DNA methylation signatures in blood associated with pan-cancer, at or near SASH1, COL11A2, AXL, and LINC00340. Three of these signals were present up to 5 years prior to cancer diagnosis, highlighting the potential clinical utility of whole blood DNA methylation analysis in cancer surveillance.Electronic supplementary materialThe online version of this article (doi:10.1186/s13148-016-0172-y) contains supplementary material, which is available to authorized users.
Highlights
A key focus in cancer research is the discovery of biomarkers that accurately diagnose early lesions in non-invasive tissues
The top 1000 probes with the highest standard deviations were assessed with unsupervised hierarchical clustering, to determine if the most variable CpG sites combined were associated with cancer status
We identified one novel epigenome-wide significant pan-cancer differentially methylated position (DMP) at a false discovery rate (FDR) threshold of 10 %, located in an intergenic region upstream of a known tumour suppressor gene SASH1, and three suggestive pan-cancer-associated signals in the genes COL11A2 and AXL, and in LINC00340, two of which have previously been linked to cancer (AXL, LINC00340)
Summary
A key focus in cancer research is the discovery of biomarkers that accurately diagnose early lesions in non-invasive tissues. One key area of focus is the development of cancer biomarkers in non-invasive tissues, such as peripheral blood or serum, which can accurately diagnose early lesions, and improve survival, and even identify individuals at risk [4,5,6]. DNA methylation is a molecular mark that has a great potential as biomarker for early cancer detection in noninvasive tissues It is a relatively stable epigenetic mark that can be influenced by DNA sequence variation, and environmental factors and stochastic changes that occur over a lifetime [7,8,9,10,11]. Epigenetic changes that occur in carcinogenesis can be detected in early neoplastic tissues, as well as tumour-derived DNA in plasma or serum of patients [21]
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