DNA methylation in ductal carcinoma in situ related with future development of invasive breast cancer

Abstract

BackgroundDuctal 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.ResultsWe 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 methylation (P < 0.01 and median |∆β| > 0.1) in these cases compared with age-matched subjects without invasive disease. The set of differentially methylated CpG loci associated with disease progression was enriched in homeobox-containing genes (P = 1.3E-09) and genes involved with limb morphogenesis (P = 1.0E-05). In an independent cohort, a subset of genes with progression-related differential methylation between DCIS and invasive breast cancer were confirmed. Further, the functional relevance of these genes’ regulation by methylation was demonstrated in early stage breast cancers from The Cancer Genome Atlas database.ConclusionsThis work contributes to the understanding of epigenetic alterations that occur in DCIS and illustrates the potential of DNA methylation as markers of DCIS progression.Electronic supplementary materialThe online version of this article (doi:10.1186/s13148-015-0094-0) contains supplementary material, which is available to authorized users.

Effects of ionizing radiation on DNA methylation: from experimental biology to clinical applications

“…DNA methylation profiles within specific genes can affect their transcriptional patterns and can be altered by exogenous stressors. Given that DNA hypermethylation-induced silencing of tumor-suppressor genes and hypomethylation-induced activation of oncogenes have been described in virtually all human cancers and are considered driving mechanisms of carcinogenesis (Portela & Esteller, 2010; Heyn & Esteller, 2012; Jones, 2012; Johnson et al, 2015; Nüsgen et al, 2015), the potential for IR-induced changes in gene-specific DNA methylation that affect changes in expression are critically important.…”

Identifying progression predictors of breast ductal carcinoma in situ

“…Downregulation of expression of epithelial cell-related genes also suggests that hypermethylation of gene promoters may play a role in this step of DCIS progression 22. Using genome-wide DNA methylation arrays, Johnson et al 23 uncovered DCIS-specific alterations in DNA methylation that differ from those in IDC. In conclusion, these studies provide evidence of a general shared genetic susceptibility between DCIS and IDC, overlain with a degree of alteration to DNA methylation patterns that might contribute to driving changes in gene expression that promote progression.…”

Concordance of DNA methylation profiles between breast core biopsy and surgical excision specimens containing ductal carcinoma in situ (DCIS)

“…Promoter methylation is related with repression of gene transcription, while gene-body methylation is often associated with increased gene expression 6,7 . Perturbation of DNA methylation is common in breast cancer 8–10 . Previously, we characterized the landscape of DNA methylation alterations in DCIS lesions and identified DNA methylation biomarkers related with risk of developing invasive breast cancer 9,10 .…”

“…Perturbation of DNA methylation is common in breast cancer 8–10 . Previously, we characterized the landscape of DNA methylation alterations in DCIS lesions and identified DNA methylation biomarkers related with risk of developing invasive breast cancer 9,10 .…”

“…We examined DNA methylation profiles in matched specimen pairs from 13 subjects enrolled in the New Hampshire Mammography Network (NHMN) and treated at Dartmouth-Hitchcock Medical Center 10,16 .…”