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 Leo 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 journalArticle

4 Citations (Scopus)

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 1 2018

Fingerprint

Neoplasm Genes
Telomere
DNA Methylation
Neoplasms
Leukocytes
Methylation
Maintenance
Telomere Shortening
Proportional Hazards Models
Epigenomics
DNA Repair
Genes
Melanoma
Prostatic Neoplasms
Carcinogenesis
Logistic Models
Research Personnel
Skin

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Joyce, Brian T. ; Zheng, Yinan ; Nannini, Drew ; Zhang, Zhou ; Liu, Lei ; Gao, Tao ; Kocherginsky, Masha ; Murphy, Robert Leo ; Yang, Hushan ; Achenbach, Chad J ; Roberts, Lewis R. ; Hoxha, Mirjam ; Shen, Jincheng ; Vokonas, Pantel ; Schwartz, Joel ; Baccarelli, Andrea ; Hou, Lifang. / DNA methylation of telomere-related genes and cancer risk. In: Cancer Prevention Research. 2018 ; Vol. 11, No. 8. pp. 511-522.
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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.",
author = "Joyce, {Brian T.} and Yinan Zheng and Drew Nannini and Zhou Zhang and Lei Liu and Tao Gao and Masha Kocherginsky and Murphy, {Robert Leo} and Hushan Yang and Achenbach, {Chad J} and Roberts, {Lewis R.} and Mirjam Hoxha and Jincheng Shen and Pantel Vokonas and Joel Schwartz and Andrea Baccarelli and Lifang Hou",
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Joyce, BT, Zheng, Y, Nannini, D, Zhang, Z, Liu, L, Gao, T, Kocherginsky, M, Murphy, RL, Yang, H, Achenbach, CJ, Roberts, LR, Hoxha, M, Shen, J, Vokonas, P, Schwartz, J, Baccarelli, A & Hou, L 2018, 'DNA methylation of telomere-related genes and cancer risk', Cancer Prevention Research, vol. 11, no. 8, pp. 511-522. https://doi.org/10.1158/1940-6207.CAPR-17-0413

DNA methylation of telomere-related genes and cancer risk. / Joyce, Brian T.; Zheng, Yinan; Nannini, Drew; Zhang, Zhou; Liu, Lei; Gao, Tao; Kocherginsky, Masha; Murphy, Robert Leo; Yang, Hushan; Achenbach, Chad J; Roberts, Lewis R.; Hoxha, Mirjam; Shen, Jincheng; Vokonas, Pantel; Schwartz, Joel; Baccarelli, Andrea; Hou, Lifang.

In: Cancer Prevention Research, Vol. 11, No. 8, 01.08.2018, p. 511-522.

Research output: Contribution to journalArticle

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T1 - DNA methylation of telomere-related genes and cancer risk

AU - Joyce, Brian T.

AU - Zheng, Yinan

AU - Nannini, Drew

AU - Zhang, Zhou

AU - Liu, Lei

AU - Gao, Tao

AU - Kocherginsky, Masha

AU - Murphy, Robert Leo

AU - Yang, Hushan

AU - Achenbach, Chad J

AU - Roberts, Lewis R.

AU - Hoxha, Mirjam

AU - Shen, Jincheng

AU - Vokonas, Pantel

AU - Schwartz, Joel

AU - Baccarelli, Andrea

AU - Hou, Lifang

PY - 2018/8/1

Y1 - 2018/8/1

N2 - 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.

AB - 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.

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