Abstract
Simple SummaryAs known breast cancer risk factors do not accurately predict the risk of developing breast cancer, breast cancer screening is still based solely on age. At the interface between environmental exposures and gene expression, DNA methylation patterns are potential biomarkers for assessing breast cancer risk, thus allowing for implementation of personalized screening and risk-reducing strategies. We used a comprehensive high-throughput DNA methylation assay in an unprecedented study design of normal breast epithelial tissue to detect methylation changes that are causally related to breast cancer occurrence and replicated our analyses in two independent datasets of normal breast tissue and blood. We identified several methylation differences in cancer-related genes, some of which overlapped between normal breast tissue and blood and were reported in previous studies. Our findings warrant further investigation on novel biomarkers for identifying women that will benefit the most from breast cancer screening.Differential DNA methylation is a potential marker of breast cancer risk. Few studies have investigated DNA methylation changes in normal breast tissue and were largely confounded by cancer field effects. To detect methylation changes in normal breast epithelium that are causally associated with breast cancer occurrence, we used a nested case–control study design based on a prospective cohort of patients diagnosed with a primary invasive hormone receptor-positive breast cancer. Twenty patients diagnosed with a contralateral breast cancer (CBC) were matched (1:1) with 20 patients who did not develop a CBC on relevant risk factors. Differentially methylated Cytosine-phosphate-Guanines (CpGs) and regions in normal breast epithelium were identified using an epigenome-wide DNA methylation assay and robust linear regressions. Analyses were replicated in two independent sets of normal breast tissue and blood. We identified 7315 CpGs (FDR < 0.05), 52 passing strict Bonferroni correction (p < 1.22 × 10−7) and 43 mapping to known genes involved in metabolic diseases with significant enrichment (p < 0.01) of pathways involving fatty acids metabolic processes. Four differentially methylated genes were detected in both site-specific and regions analyses (LHX2, TFAP2B, JAKMIP1, SEPT9), and three genes overlapped all three datasets (POM121L2, KCNQ1, CLEC4C). Once validated, the seven differentially methylated genes distinguishing women who developed and who did not develop a sporadic breast cancer could be used to enhance breast cancer risk-stratification, and allow implementation of targeted screening and preventive strategies that would ultimately improve breast cancer prognosis.
Highlights
As a major and increasing worldwide public health burden, breast cancer prompts the need for identification of early breast tissue molecular alterations that could be used for risk-tailored early diagnostic and effective primary prevention strategies
4 cm from primary breast tumors [5,6]. These molecular alterations may reflect both precancerous alterations that led to breast cancer development and alterations induced by the microenvironment of the adjacent developing cancer [7]
Distribution of contralateral breast cancer risk factors was similar for cases and controls
Summary
As a major and increasing worldwide public health burden, breast cancer prompts the need for identification of early breast tissue molecular alterations that could be used for risk-tailored early diagnostic and effective primary prevention strategies. Many DNA methylation studies have been conducted on blood samples, and the detected methylation marks were not consistent across studies, even when these marks were validated and reproduced in independent datasets within the same study These inconsistencies can mainly be explained by methodological biases [4] but can suggest some limitations when considering blood samples for detecting methylation marks of tissue-specific cancers. Genetic and epigenetic field effects in histologically normal-appearing tissue adjacent to cancer have been reported as far as 4 cm from primary breast tumors [5,6]. These molecular alterations may reflect both precancerous alterations that led to breast cancer development and alterations induced by the microenvironment of the adjacent developing cancer [7]
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