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.
Highlights
Ductal carcinoma in situ (DCIS) is a heterogeneous, pre-invasive lesion associated with an increased risk for future invasive ductal carcinoma
We have identified epigenetic changes in ER positive DCIS that may contribute to increased risk of developing invasive breast cancer
There was no significant enrichment for membership in either methylation cluster for DCIS grade, subsequent diagnosis of invasive breast cancer, or subject age
Summary
Ductal carcinoma in situ (DCIS) is a heterogeneous, pre-invasive lesion associated with an increased risk for future invasive ductal carcinoma. 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. Identifying differential risks of developing invasive breast cancer among DCIS patients may improve patient outcomes and reduce healthcare costs. DNA methylation deregulation occurs early in carcinogenesis, the patterns of epigenetic alterations associated with development of invasive disease remain unclear. DNA methylation alterations are potential markers for DCIS outcome prediction and may identify cellular changes that modulate tumor progression. The identification of DNA methylation alterations that can inform risk of subsequent invasive disease has the potential to both impact clinical treatment decisions and improve our understanding of cancer progression
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