DNA Methylation of Telomere Biology Genes and Cancer Risk

Background: Telomeres maintain genomic stability and regulate cellular senescence. Numerous studies examined blood leukocyte telomere length (LTL) and cancer risk, including our own which identified a dynamic relationship between LTL and cancer risk over time. Other studies have suggested that cancer cells are able to hijack telomere maintenance mechanisms (e.g., telomerase) to circumvent the Hayflick limit, which will otherwise induce senescence and limit cancer cells’ ability to multiply. As DNA methylation dysregulation is a known epigenetic hallmark of cancer, our objective was to understand whether DNA methylation of telomere-related genes (TRGs) is associated with cancer risk and LTL. Methods: We studied 915 blood measurements from 491 participants in the Normative Aging Study taken between 1999 and 2013. All participants were cancer-free at each blood donation, randomly selected for DNA methylation profiling using the Illumina 450K array, and analyzed by cancer status (125 cancer cases diagnosed during follow up and 366 cancer-free controls). We examined 1,956 CpG sites on 98 TRGs using FDR-corrected linear models to identify differentially methylated CpGs at the first blood draw only, followed by mixed-effect models using our full data to determine the final CpG sites of interest for Cox models of cancer risk. Our secondary analyses of these sites explored trajectories of DNA methylation by cancer status, models stratified by interval between blood collection and cancer diagnosis, and joint associations of DNA methylation and cancer status on LTL. Results: We discovered 167 CpG sites at the first blood draw, and 10 across the full follow up, which were associated with cancer status at FDR <0.05. Methylation of one CpG on each of CDC73, NSMCE2, and RPA1 was associated with decreased cancer risk. Methylation of one CpG on each of DCLRE1C, DDB1, H2AFY, HNRNPA2B1, and TEP1 as well as two CpGs on TERF2 was associated with increased cancer risk. DNA methylation trajectory at CpGs on three genes was significantly different across cancer status, and six CpGs on five genes were positively associated with cancer incidence 4-8 years pre-diagnosis. Finally one CpG on NSMCE2 and two on TERF2 were associated with LTL in cancer-free subjects, with the methylation-LTL association significantly different in subjects who later developed cancer for one CpG on TERF2. Conclusion: These findings suggest that methylation changes in TRGs may be a mechanism by which cancer cells alter telomere length, undermine genomic stability, and protect themselves from senescence. Future studies should confirm these findings, and explore these CpG sites and genes as potential early detection biomarkers and therapeutic targets.