title: Genome-wide DNA methylation profiles in progression to in situ and invasive carcinoma of the breast with impact on gene transcription and prognosis.
abstract: BACKGROUND
  Ductal 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.
  
  
  RESULTS
  We 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 5,000 genes. Changes between DCIS and invasive breast carcinoma involve around 1,000 genes. In tumors, DNA methylation is associated with gene expression of almost 3,000 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.
  
  
  CONCLUSIONS
  This 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.
authors.forename: Thomas
authors.initials: T
authors.lastname: Fleischer
authors.forename: Arnoldo
authors.initials: A
authors.lastname: Frigessi
authors.forename: Kevin C
authors.initials: KC
authors.lastname: Johnson
authors.forename: Hege
authors.initials: H
authors.lastname: Edvardsen
authors.forename: Nizar
authors.initials: N
authors.lastname: Touleimat
authors.forename: Jovana
authors.initials: J
authors.lastname: Klajic
authors.forename: Margit Lh
authors.initials: ML
authors.lastname: Riis
authors.forename: Vilde D
authors.initials: VD
authors.lastname: Haakensen
authors.forename: Fredrik
authors.initials: F
authors.lastname: Wärnberg
authors.forename: Bjørn
authors.initials: B
authors.lastname: Naume
authors.forename: Aslaug
authors.initials: A
authors.lastname: Helland
authors.forename: Anne-Lise
authors.initials: AL
authors.lastname: Børresen-Dale
authors.forename: Jörg
authors.initials: J
authors.lastname: Tost
authors.forename: Brock C
authors.initials: BC
authors.lastname: Christensen
authors.affiliation: Department of Genetics, Institute for Cancer Research, OUS Radiumhospitalet, Montebello, Oslo, 0310, Norway. v.n.kristensen@medisin.uio.no.
authors.forename: Vessela N
authors.initials: VN
authors.lastname: Kristensen
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics*; D018270:Carcinoma, Ductal, Breast / Q000235:genetics*; D002285:Carcinoma, Intraductal, Noninfiltrating / Q000235:genetics*; D018899:CpG Islands; D019175:DNA Methylation; D018450:Disease Progression; D044127:Epigenesis, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D011379:Prognosis; D016019:Survival Analysis; D014158:Transcription, Genetic