Abstract 2264: Telomere biology gene methylation and cancer risk
Authors: Joyce Brian T. , Li Yang , Zheng Yinan , Liu Lei , Yang Hushan , Achenbach Chad , Vokonas Pantel , Schwartz Joel , Baccarelli Andrea , Hou Lifang 
Published: July 2017

Background: Telomeres maintain genomic stability and regulate cellular senescence. Numerous studies have examined blood telomere length (BTL) and cancer risk, including our own which previously identified a dynamic relationship between BTL and cancer risk over time: Relative to subjects who remained cancer-free, those who later developed cancer experienced accelerated telomere shortening until 3-4 years prior to cancer diagnosis/censoring, at which point BTL in the incident cancer group stabilized. Other studies have suggested that cancer cells are able to hijack telomere maintenance mechanisms (e.g., telomerase) in order 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 biology genes is associated with cancer risk and BTL.

Methods: We studied 915 blood measurements from 491 subjects in the Normative Aging Study taken between 1999 and 2013, who were cancer free in 1999 and randomly selected for whole-epigenome DNA methylation profiling using the Illumina 450K BeadChip array. Among these subjects, 125 cases developed cancer and 366 controls remained cancer free for our entire follow up (median 10.1 years). Our analysis focused on 2,731 CpG sites on 142 genes related to telomere length maintenance. We used linear models to identify CpGs differentially methylated by cancer status at the first blood draw only, followed by mixed models using our full data to determine the final CpG sites of interest for Cox models of cancer risk, and another set of mixed models to compare trajectories over time of methylation in cancer patients vs. controls. Finally an additional mixed model explored the temporal relationship between methylation measured at the first visit and BTL measured at the second visit.

Results: Our screening identified 167 CpG sites, 10 of which were associated with time-dependent cancer risk at FDR &lt;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 three CpGs was significantly different across cancer status (cg20772347 on DDB1, cg23157637 on TEP1, and cg04818274 on TERF2). One CpG on NSMCE2 and one on TERF2 were associated with BTL in cancer-free subjects, while another CpG on TERF2 was associated with BTL in subjects who later developed cancer.

Conclusion: These findings suggest that methylation changes in telomere maintenance genes may be a mechanism by which cancer cells alter telomere length, thus undermining genomic stability and protecting cancer cells from senescence. Future studies should confirm these findings, and explore these CpG sites and genes as potential early detection biomarkers and therapeutic targets.

Citation Format: Brian T. Joyce, Yang Li, Yinan Zheng, Lei Liu, Hushan Yang, Chad Achenbach, Pantel Vokonas, Joel Schwartz, Andrea Baccarelli, Lifang Hou. Telomere biology gene methylation and cancer risk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2264. doi:10.1158/1538-7445.AM2017-2264