Longitudinal Study of DNA Methylation of Inflammatory Genes and Cancer Risk.
BACKGROUND
Chronic inflammation plays a key role in cancer etiology. DNA methylation modification, one of the epigenetic mechanisms regulating gene expression, is considered a hallmark of cancer. Human and animal models have identified numerous links between DNA methylation and inflammatory biomarkers. Our objective was to prospectively and longitudinally examine associations between methylation of four inflammatory genes and cancer risk.


METHODS
We included 795 Normative Aging Study participants with blood drawn one to four times from 1999 to 2012 (median follow-up, 10.6 years). Promoter DNA methylation of IL6, ICAM-1, IFN, and TLR2 in blood leukocytes was measured using pyrosequencing at multiple CpG sites and averaged by gene for data analysis. We used Cox regression models to examine prospective associations of baseline and time-dependent methylation with cancer risk and compared mean methylation differences over time between cancer cases and cancer-free participants.


RESULTS
Baseline IFN hypermethylation was associated with all-cancer (HR, 1.49; P = 0.04) and prostate cancer incidence (HR, 1.69; P = 0.02). Baseline ICAM-1 and IL6 hypermethylation were associated with prostate cancer incidence (HR, 1.43; P = 0.02; HR, 0.70; P = 0.03, respectively). In our time-dependent analyses, IFN hypermethylation was associated with all-cancer (HR, 1.79; P = 0.007) and prostate cancer (HR, 1.57; P = 0.03) incidence; and ICAM-1 and IL6 hypermethylation were associated with prostate cancer incidence (HR, 1.39; P = 0.02; HR, 0.69; P = 0.03, respectively). We detected significant ICAM-1 hypermethylation in cancer cases (P = 0.0003) 10 to 13 years prediagnosis.


CONCLUSIONS
Hypermethylation of IFN and ICAM-1 may play important roles in early carcinogenesis, particularly that of prostate cancer.


CONCLUSIONS
These methylation changes could inform the development of early detection biomarkers and potential treatments of inflammation-related carcinogenesis.
Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois. Division of Epidemiology/Biostatistics, School of Public Health, University of Illinois-Chicago, Chicago, Illinois. b-joyce@northwestern.edu.
Brian Thomas
BT
Joyce
Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
Tao
T
Gao
Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois. Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
Lei
L
Liu
Institute for Public Health and Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
Yinan
Y
Zheng
Department of Biomedical Engineering, Northwestern University, Chicago, Illinois.
Siran
S
Liu
Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
Wei
W
Zhang
Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois. Department of Medical Social Sciences, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
Frank
F
Penedo
Vanderbilt University Medical Center, Nashville, Tennessee.
Qi
Q
Dai
Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts.
Joel
J
Schwartz
Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts.
Andrea A
AA
Baccarelli
Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois. Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
Lifang
L
Hou
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D063646:Carcinogenesis / Q000235:genetics*; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics*; D018572:Disease-Free Survival; D005544:Forecasting; D006801:Humans; D015994:Incidence; D007249:Inflammation / Q000235:genetics* / Q000378:metabolism; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011446:Prospective Studies; D012307:Risk Factors; D015996:Survival Rate / Q000639:trends; D014481:United States / Q000453:epidemiology; D055815:Young Adult
D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm