DNA methylation of telomere-related genes and cancer risk

Brian T. Joyce*, Yinan Zheng, Drew Nannini, Zhou Zhang, Lei Liu, Tao Gao, Masha Kocherginsky, Robert Murphy, Hushan Yang, Chad J. Achenbach, Lewis R. Roberts, Mirjam Hoxha, Jincheng Shen, Pantel Vokonas, Joel Schwartz, Andrea Baccarelli, Lifang Hou

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

Researchers hypothesized that telomere shortening facilitates carcinogenesis. Previous studies found inconsistent associations between blood leukocyte telomere length (LTL) and cancer. Epigenetic reprogramming of telomere maintenance mechanisms may help explain this inconsistency. We examined associations between DNA methylation in telomere-related genes (TRG) and cancer. We analyzed 475 participants providing 889 samples 1 to 3 times (median follow-up, 10.1 years) from 1999 to 2013 in the Normative Aging Study. All participants were cancer-free at each visit and blood leukocytes profiled using the Illumina 450K array. Of 121 participants who developed cancer, 34 had prostate cancer, 10 melanoma, 34 unknown skin malignancies, and 43 another cancer. We examined 2,651 CpGs from 80 TRGs and applied a combination of Cox and mixed models to identify CpGs prospectively associated with cancer (at FDR < 0.05). We also explored trajectories of DNA methylation, logistic regression stratified by time to diagnosis/censoring, and cross-sectional models of LTL at first blood draw. We identified 30 CpGs on 23 TRGs whose methylation was positively associated with cancer incidence (b ¼ 1.0–6.93) and one protective CpG in MAD1L1 (b ¼ 0.65), of which 87% were located in TRG promoters. Methylation trajectories of 21 CpGs increased in cancer cases relative to controls; at 4 to 8 years prediagnosis/censoring, 17 CpGs were positively associated with cancer. Three CpGs were cross-sectionally associated with LTL. TRG methylation may be a mechanism through which LTL dynamics reflect cancer risk. Future research should confirm these findings and explore potential mechanisms underlying these findings, including telomere maintenance and DNA repair dysfunction.

Original languageEnglish (US)
Pages (from-to)511-522
Number of pages12
JournalCancer Prevention Research
Volume11
Issue number8
DOIs
StatePublished - Aug 2018

Funding

The Normative Aging Study is supported by the Epidemiology Research and Information Center of the U.S. Department of Veterans Affairs (NIEHS R01- ES015172) and is a research component of the Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC). L. Hou received additional support from the Northwestern University Robert H. Lurie Comprehensive Cancer Center Rosenberg Research Fund. L. Hou, R. Murphy, and L.R. Roberts also received support from the NCI: 1U54CA221205-01 and D43 TW009575. A. Baccarelli and J. Schwartz received additional support from the National Institute of Environmental Health Sciences; NIEHS R01-ES021733, NIEHS R01-ES015172, NIEHS-R01ES025225, NIEHS P30-ES009089, and NIEHS P30-ES00002. The Normative Aging Study is supported by the Epidemiology Research and Information Center of the U.S. Department of Veterans Affairs (NIEHS R01-ES015172) and is a research component of the Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC). L. Hou received additional support from the North-western University Robert H. Lurie Comprehensive Cancer Center Rosenberg Research Fund. L. Hou, R. Murphy, and L.R. Roberts also received support from the NCI: 1U54CA221205-01 and D43 TW009575. A. Baccarelli and J. Schwartz received additional support from the National Institute of Environmental Health Sciences; NIEHS R01-ES021733, NIEHS R01-ES015172, NIEHS-R01ES025225, NIEHS P30-ES009089, and NIEHS P30-ES00002.

ASJC Scopus subject areas

  • General Medicine

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