Abstract
BackgroundWe examined whether differences in tumor DNA methylation were associated with more aggressive hormone receptor-negative breast cancer in an ethnically diverse group of patients in the Breast Cancer Care in Chicago (BCCC) study and using data from The Cancer Genome Atlas (TCGA).ResultsDNA was extracted from formalin-fixed, paraffin-embedded samples on 75 patients (21 White, 31 African-American, and 23 Hispanic) (training dataset) enrolled in the BCCC. Hormone receptor status was defined as negative if tumors were negative for both estrogen and progesterone (ER/PR) receptors (N = 22/75). DNA methylation was analyzed at 1505 CpG sites within 807 gene promoters using the Illumina GoldenGate assay. Differential DNA methylation as a predictor of hormone receptor status was tested while controlling for false discovery rate and assigned to the gene closest to the respective CpG site. Next, those genes that predicted ER/PR status were validated using TCGA data with respect to DNA methylation (validation dataset), and correlations between CpG methylation and gene expression were examined. In the training dataset, 5.7 % of promoter mean methylation values (46/807) were associated with receptor status at P < 0.05; for 88 % of these (38/46), hypermethylation was associated with receptor-positive disease. Hypermethylation for FZD9, MME, BCAP31, HDAC9, PAX6, SCGB3A1, PDGFRA, IGFBP3, and PTGS2 genes most strongly predicted receptor-positive disease. Twenty-one of 24 predictor genes from the training dataset were confirmed in the validation dataset. The level of DNA methylation at 19 out 22 genes, for which gene expression data were available, was associated with gene activity.ConclusionsHigher levels of promoter methylation strongly correlate with hormone receptor positive status of breast tumors. For most of the genes identified in our training dataset as ER/PR receptor status predictors, DNA methylation correlated with stable gene expression level. The predictors performed well when evaluated on independent set of samples, with different racioethnic distribution, thus providing evidence that this set of DNA methylation biomarkers will likely generalize to prospective patient samples.Electronic supplementary materialThe online version of this article (doi:10.1186/s13148-016-0184-7) contains supplementary material, which is available to authorized users.
Highlights
We examined whether differences in tumor DNA methylation were associated with more aggressive hormone receptor-negative breast cancer in an ethnically diverse group of patients in the Breast Cancer Care in Chicago (BCCC) study and using data from The Cancer Genome Atlas (TCGA)
The level of DNA methylation is higher in estrogen and progesterone (ER/PR)-positive tumors in the training dataset We tested if associations can be drawn between the levels of DNA methylation and hormone receptor ER/ PR status in an ethnically diverse patient cohort with invasive breast cancer disease
DNA methylation at disease predictor genes in the validation dataset We examined whether the 25 predictive gene methylation markers identified through the BCCC study would predict hormone receptor status in data from The Cancer Genome Atlas (TCGA)
Summary
We examined whether differences in tumor DNA methylation were associated with more aggressive hormone receptor-negative breast cancer in an ethnically diverse group of patients in the Breast Cancer Care in Chicago (BCCC) study and using data from The Cancer Genome Atlas (TCGA). ER/PR-negative tumors are of particular interest because they tend to be the most aggressive form and lack targets for hormone therapy. These new DNA methylation-based characteristics had a potential to contribute prognostic value in breast cancer management. Prior studies using panels of DNA methylation markers, are plagued by lack of reproducibility, in part because these studies tend to focus on the top-most performing markers [11], as opposed to genome-wide association. The prevalence of certain markers in particular cohort populations was not taken into account, as race and ethnicity were either not reported or lacking Hispanic and African-American patient population [8,9,10, 12]
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