Genome-wide DNA methylation profiles in progression to in situand invasive carcinoma of the breast with impact on gene transcription and prognosis

Abstract

BackgroundDuctal carcinoma in situ (DCIS) of the breast is a precursor of invasive breast carcinoma. DNA methylation alterations are thought to be an early event in progression of cancer, and may prove valuable as a tool in clinical decision making and for understanding neoplastic development.ResultsWe generate genome-wide DNA methylation profiles of 285 breast tissue samples representing progression of cancer, and validate methylation changes between normal and DCIS in an independent dataset of 15 normal and 40 DCIS samples. We also validate a prognostic signature on 583 breast cancer samples from The Cancer Genome Atlas. Our analysis reveals that DNA methylation profiles of DCIS are radically altered compared to normal breast tissue, involving more than 5,000 genes. Changes between DCIS and invasive breast carcinoma involve around 1,000 genes. In tumors, DNA methylation is associated with gene expression of almost 3,000 genes, including both negative and positive correlations. A prognostic signature based on methylation level of 18 CpGs is associated with survival of breast cancer patients with invasive tumors, as well as with survival of patients with DCIS and mixed lesions of DCIS and invasive breast carcinoma.ConclusionsThis work demonstrates that changes in the epigenome occur early in the neoplastic progression, provides evidence for the possible utilization of DNA methylation-based markers of progression in the clinic, and highlights the importance of epigenetic changes in carcinogenesis.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-014-0435-x) contains supplementary material, which is available to authorized users.

Racial differences in genome-wide methylation profiling and gene expression in breast tissues from healthy women

“…33 In this study, 10% of the DM CpGs were significantly correlated with the gene expression. This figure is similar to previous genome-wide studies in primary fibroblast samples (8.9%), 34 ductal carcinoma in situ (DCIS) of the breast (10.5%) 35 and considerably higher than other studies in breast tumors (The Cancer Genome Atlas (TCGA) breast cancer data set) (3.3%) (35). Taken together, these data suggest that associations of methylation to gene expression vary by tissue type.…”

Ductal carcinoma in situ of the breast: the importance of morphologic and molecular interactions

“…In view of these findings, the analysis of such a gene panel through quantitative methylation might represent a tool for predicting disease progression. These data have been confirmed by Fleischer et al who recently reported the DNA methylation profiles of a breast cancer progression series, including normal breast tissue, DCIS, invasive carcinoma, and mixed lesions [54]. In agreement with previous studies, most of the aberrations in the epigenetic profile were observed already in the pre-invasive stage.…”

“…Recently, Fleischer and colleagues also investigated methylation patterns during progression of breast cancer [54].…”

“…The authors concluded that most of the aberrations in the epigenetic profile were observed already in the pre-invasive DCIS stage, while the changes between DCIS and IBC were comparably modest [54]. 15 6.…”

“…In agreement with previous studies, most of the aberrations in the epigenetic profile were observed already in the pre-invasive stage. Of note the authors also described a signature comprising DNA methylation levels of 18 CpGs that was prognostic for breast cancer patients with invasive tumors as well as for patients with DCIS and mixed lesions of DCIS and invasive breast carcinoma [54].…”