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However, its impact on tumor development is not fully determined, and its potential as a diagnostic biomarker remains to be validated. Methylation profiling of invasive breast carcinoma has been largely explored. Conversely, very little and sparse information is available on early-stage breast cancer. To gain insight into the epigenetic switches that may promote and\/or contribute to the initial neoplastic events during breast carcinogenesis, we have analyzed the DNA methylation profile of ductal carcinoma <jats:italic>in situ<\/jats:italic>, a premalignant breast lesion with a great potential to progress toward invasive carcinoma.<\/jats:p>\n                     <\/jats:sec><jats:sec>\n                        <jats:title>Methods<\/jats:title>\n                        <jats:p>We have utilized a comprehensive and sensitive array-based DNA mapping technique, the methylated-CpG island recovery assay, to profile the DNA methylation pattern in ductal carcinoma <jats:italic>in situ<\/jats:italic>. Differential methylation of CpG islands was compared genome-wide in tumor DNA versus normal DNA utilizing a statistical linear model in the LIMMA software package.<\/jats:p>\n                     <\/jats:sec><jats:sec>\n                        <jats:title>Results<\/jats:title>\n                        <jats:p>Using this approach, we have identified 108 significant CpG islands that undergo aberrant DNA methylation in ductal carcinoma <jats:italic>in situ<\/jats:italic> and stage I breast tumors, with methylation frequencies greater than or comparable with those of more advanced invasive carcinoma (50% to 93%). A substantial fraction of these hypermethylated CpG islands (32% of the annotated CpG islands) is associated with several homeobox genes, such as the <jats:italic>TLX1<\/jats:italic>, <jats:italic>HOXB13<\/jats:italic>, and <jats:italic>HNF1B<\/jats:italic> genes. Fifty-three percent of the genes hypermethylated in early-stage breast cancer overlap with known Polycomb targets and include homeobox genes and other developmental transcription factors.<\/jats:p>\n                     <\/jats:sec><jats:sec>\n                        <jats:title>Conclusions<\/jats:title>\n                        <jats:p>We have identified a series of new potential methylation biomarkers that may help elucidate the underlying mechanisms of breast tumorigenesis. More specifically, our results are suggestive of a critical role of homeobox gene methylation in the insurgence and\/or progression of breast cancer.<\/jats:p>\n                     <\/jats:sec>","DOI":"10.1186\/bcr2233","type":"journal-article","created":{"date-parts":[[2009,2,28]],"date-time":"2009-02-28T07:14:02Z","timestamp":1235805242000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":119,"title":["Methylation of homeobox genes is a frequent and early epigenetic event in breast cancer"],"prefix":"10.1186","volume":"11","author":[{"given":"Stella","family":"Tommasi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deborah L","family":"Karm","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiwei","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun","family":"Yen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerd P","family":"Pfeifer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2009,2,27]]},"reference":[{"key":"2197_CR1","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1093\/ije\/dyh414","volume":"34","author":"MD Althuis","year":"2005","unstructured":"Althuis MD, Dozier JM, Anderson WF, Devesa SS, Brinton LA: Global trends in breast cancer incidence and mortality 1973\u20131997. 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