Genome-wide DNA methylation profiles in progression to (original) (raw)
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Clinical epigenetics, 2015
Ductal carcinoma in situ (DCIS) is a heterogeneous, pre-invasive lesion associated with an increased risk for future invasive ductal carcinoma. However, accurate risk stratification for development of invasive disease and appropriate treatment decisions remain clinical challenges. DNA methylation alterations are early events in the progression of cancer and represent emerging molecular markers that may predict invasive recurrence more accurately than traditional measures of DCIS prognosis. We measured DNA methylation using the Illumina HumanMethylation450K array of estrogen-receptor positive DCIS (n = 40) and adjacent-normal (n = 15) tissues from subjects in the New Hampshire Mammography Network longitudinal breast imaging registry. We identified locus-specific methylation differences between DCIS and matched adjacent-normal tissue (95,609 CpGs, Q < 0.05). Among 40 DCIS cases, 13 later developed invasive disease and we identified 641 CpG sites that exhibited differential DNA meth...
Oncotarget, 2015
Until recently, an elevated disease risk has been ascribed to a genetic predisposition, however, exciting progress over the past years has discovered alternate elements of inheritance that involve epigenetic regulation. Epigenetic changes are heritably stable alterations that include DNA methylation, histone modifications and RNA-mediated silencing. Aberrant DNA methylation is a common molecular basis for a number of important human diseases, including breast cancer. Changes in DNA methylation profoundly affect global gene expression patterns. What is emerging is a more dynamic and complex association between DNA methylation and gene expression than previously believed. Although many tools have already been developed for analyzing genome-wide gene expression data, tools for analyzing genome-wide DNA methylation have not yet reached the same level of refinement.Here we provide an in-depth analysis of DNA methylation in parallel with gene expression data characteristics and describe t...
Identification of novel high-frequency DNA methylation changes in breast cancer
PLoS One, 2007
Recent data have revealed that epigenetic alterations, including DNA methylation and chromatin structure changes, are among the earliest molecular abnormalities to occur during tumorigenesis. The inherent thermodynamic stability of cytosine methylation and the apparent high specificity of the alterations for disease may accelerate the development of powerful molecular diagnostics for cancer. We report a genome-wide analysis of DNA methylation alterations in breast cancer. The approach efficiently identified a large collection of novel differentially DNA methylated loci (,200), a subset of which was independently validated across a panel of over 230 clinical samples. The differential cytosine methylation events were independent of patient age, tumor stage, estrogen receptor status or family history of breast cancer. The power of the global approach for discovery is underscored by the identification of a single differentially methylated locus, associated with the GHSR gene, capable of distinguishing infiltrating ductal breast carcinoma from normal and benign breast tissues with a sensitivity and specificity of 90% and 96%, respectively. Notably, the frequency of these molecular abnormalities in breast tumors substantially exceeds the frequency of any other single genetic or epigenetic change reported to date. The discovery of over 50 novel DNA methylation-based biomarkers of breast cancer may provide new routes for development of DNA methylation-based diagnostics and prognostics, as well as reveal epigenetically regulated mechanism involved in breast tumorigenesis.
DNA Methylation and Breast Cancer Risk: An Epigenome-Wide Study of Normal Breast Tissue and Blood
Cancers
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 ...
Epigenetics, 2016
The development and progression of invasive breast cancer is characterized by alterations to the genome and epigenome. However, the relationship between breast tumor characteristics, disease subtypes, and patient outcomes with the cumulative burden of these molecular alterations are not well characterized. We determined the average departure of tumor DNA methylation from adjacent normal breast DNA methylation using Illumina 450 K methylation data from 700 invasive breast tumors and 90 adjacent normal breast tissues in The Cancer Genome Atlas. From this we generated a novel summary measure of altered DNA methylation, the DNA methylation dysregulation index (MDI), and examined the relation of MDI with tumor characteristics and summary measures that quantify cumulative burden of genetic mutation and copy number alterations. Our analysis revealed that MDI was significantly associated with tumor stage (P=0.017). Across invasive breast tumor subtypes we observed significant differences in...
Candidate gene DNA methylation associations with breast cancer characteristics and tumor progression
Epigenomics, 2018
Aim: We examined methylation patterns with aggressive tumor phenotypes and investigated demographic, socioeconomic and reproductive predictors of gene methylation. Materials & methods: Pyrosequencing quantified methylation of BRCA1, EGFR, GSTM2, RASSF1, TFF1 and Sat 2. We used quantile regression models to calculate adjusted median methylation values by estrogen and progesterone receptor (ER/PR) status. Bivariate associations between participant characteristics and methylation were examined. Results: Higher percent methylation of GSTM2 was observed in ER/PR-negative compared with ER/PR-positive tumors in ductal carcinoma in situ (14 vs 2%) and invasive (35 vs 3%) tissue components. Trends in aberrant GSTM2 methylation across tissue components were stronger among ER/PR-negative tumors (p-interaction <0.001). Black women were more likely to have ER/PR-negative tumors (p = 0.01) and show hypermethylation of GSTM2 compared with other women (p = 0.05). Conclusion: GSTM2 promoter hyper...