Zongli Xu1, Dale P Sandler1, Jack A Taylor1,2. 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. Published by Oxford University Press 2019.
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. Published by Oxford University Press 2019.
Entities:
Keywords:
DNA methylation; breast cancer; genome-wide; peripheral blood; prospective study
Authors: Christina A Markunas; Dana B Hancock; Zongli Xu; Bryan C Quach; Fang Fang; Dale P Sandler; Eric O Johnson; Jack A Taylor Journal: Am J Med Genet B Neuropsychiatr Genet Date: 2020-08-17 Impact factor: 3.358