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

Thomas Fleischer, Arnoldo Frigessi, Kevin C Johnson, Hege Edvardsen, Nizar Touleimat, Jovana Klajic, Margit LH Riis, Vilde Haakensen, Fredrik Wärnberg, Bjørn Naume, Åslaug Helland, Anne-Lise Børresen-Dale, Jörg Tost, Brock C Christensen and Vessela N Kristensen

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Genome Biology 2014, 15:435  doi:10.1186/s13059-014-0435-x

Published: 22 August 2014

Abstract (provisional)

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 5000 genes. Changes between DCIS and invasive breast carcinoma involve around 1000 genes. In tumors, DNA methylation is associated with gene expression of almost 3000 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.

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