Blood DNA methylation and breast cancer: A prospective case-cohort analysis in the Sister Study
Menée à partir d'échantillons sanguins prélevés sur 1 552 femmes atteintes d'un cancer du sein et sur 1 224 témoins inclus dans la cohorte "Sister Study", puis menée à partir de données portant sur 152 patientes atteintes d'un cancer du sein et sur 177 témoins, cette étude analyse l'association entre le profil de méthylation de l'ADN circulant et le risque de développer la maladie
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.
Journal of the National Cancer Institute , article en libre accès, 2018