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J Natl Cancer Inst. 2019 Apr 15. pii: djz065. doi: 10.1093/jnci/djz065. [Epub ahead of print]

Blood DNA methylation and breast cancer: A prospective case-cohort analysis in the Sister Study.

Author information

1
Epidemiology Branch, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC.
2
Epigenetics & Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC.

Abstract

BACKGROUND:

Peripheral blood DNA methylation may be associated with breast cancer, but studies of candidate genes, global, and genome-wide DNA methylation have been inconsistent.

METHODS:

We performed an epigenome-wide study using Infinium HumanMethylation450 BeadChips with prospectively collected blood DNA samples from the Sister Study, (1552 cases, 1224 sub-cohort). Differentially methylated CpGs were identified using case-cohort proportional hazard models and replicated using deposited data from EPIC-Italy (n = 329). Correlation between methylation and time-to-diagnosis was examined using robust linear regression. Causal/consequential relationships of methylation to breast cancer was examined by Mendelian randomization using OncoArray 500K SNP data. All statistical tests were two-sided.

RESULTS:

We identified 9601 CpG markers associated with invasive breast cancer (false discovery rate FDR q < 0.01), with 510 meeting a strict Bonferroni correction threshold (10-7). 2095 of these CpGs replicated in the independent EPIC-Italy dataset, including 144 meeting the Bonferroni threshold. Sister Study women who developed ductal carcinoma in situ had methylation similar to non-cases. Most (1501; 71.6%) differentially methylated CpGs (dmCpGs) showed lower methylation in invasive cases. In case-only analysis methylation was statistically significantly associated (FDR q < 0.05) with time-to-diagnosis for 892 (42.6%) of the dmCpGs. Analyses based on genetic association suggest that methylation differences are likely a consequence rather than a cause of breast cancer. Pathway analysis shows enrichment of breast cancer-related gene pathways, and dmCpGs are overrepresented in known breast cancer susceptibility genes.

CONCLUSIONS:

Our findings suggest that DNA methylation profile of blood starts to change in response to invasive breast cancer years before the tumor is clinically detected.

KEYWORDS:

DNA methylation; breast cancer; genome-wide; peripheral blood; prospective study

PMID:
30989176
DOI:
10.1093/jnci/djz065

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