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

被引:51
作者
Johnson, Kevin C. [1 ,2 ]
Koestler, Devin C. [3 ]
Fleischer, Thomas [4 ,5 ]
Chen, Panpan [1 ,2 ]
Jenson, Erik G. [6 ]
Marotti, Jonathan D. [6 ]
Onega, Tracy [2 ,7 ,8 ]
Kristensen, Vessela N. [4 ,5 ,9 ]
Christensen, Brock C. [1 ,2 ,10 ]
机构
[1] Geisel Sch Med Dartmouth, Dept Pharmacol & Toxicol, Hanover, NH 03755 USA
[2] Geisel Sch Med Dartmouth, Dept Epidemiol, Hanover, NH 03755 USA
[3] Univ Kansas, Med Ctr, Dept Biostat, Kansas City, KS 66103 USA
[4] Oslo Univ Hosp, Radiumhosp, Dept Genet, Inst Canc Res, Oslo, Norway
[5] Univ Oslo, Inst Clin Med, KG Jebsen Ctr Breast Canc, Fac Med, Oslo, Norway
[6] Geisel Sch Med Dartmouth, Dept Pathol, Hanover, NH 03755 USA
[7] Geisel Sch Med Dartmouth, Dept Data Sci, Hanover, NH 03755 USA
[8] Geisel Sch Med Dartmouth, Dartmouth Inst, Lebanon, NH 03766 USA
[9] Akershus Hosp, Div Med, Dept Clin Mol Biol EpiGen, Lorenskog, Norway
[10] Geisel Sch Med Dartmouth, Dept Community & Family Med, Hanover, NH 03755 USA
关键词
Breast; Methylation; Array; DCIS; Cancer; TCGA; CLASS DISCOVERY; GENE; GENOME; EXPRESSION; RISK; FREQUENT; HYPERMETHYLATION; IDENTIFICATION; TRANSCRIPTION; PROGRESSION;
D O I
10.1186/s13148-015-0094-0
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Background: 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. Results: 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 methylation (P < 0.01 and median \Delta beta\ > 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. Conclusions: This work contributes to the understanding of epigenetic alterations that occur in DCIS and illustrates the potential of DNA methylation as markers of DCIS progression.
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页数:12
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