title: Ductal carcinoma in situ and the emergence of diversity during breast cancer evolution.
abstract: OBJECTIVE
  Human invasive breast cancers (IBC) show enormous histologic and biological diversity. This study comprehensively evaluated diversity in ductal carcinoma in situ (DCIS), the immediate precursors of IBCs.
  
  
  METHODS
  The extent of diversity for conventional histologic grade and standard prognostic biomarkers assessed by immunohistochemistry was evaluated in a series of pure DCIS (n = 200) compared with a contemporaneous series of IBCs (n = 200). A subset of the DCIS (n = 25) was evaluated by DNA microarrays for the presence of luminal, basal, and erbB2 intrinsic subtypes. The extent of diversity within individual cases of DCIS (n = 120) was determined by assessing multiple regions independently for histologic (nuclear) grade and several biomarkers by immunohistochemistry, which approximate microarrays in determining intrinsic subtypes.
  
  
  RESULTS
  DCIS showed a broad distribution of conventional histologic grades and standard biomarkers ranging from well to poorly differentiated, nearly identical to IBCs. Microarrays showed the same intrinsic subtypes in DCIS as in IBCs. However, higher resolution analysis showed that multiple histologic grades, biomarker phenotypes, and intrinsic subtypes often coexist within the same DCIS, and these diverse regions probably compete for dominance. Diversity within cases of DCIS was highly correlated with mutated p53 (P = 0.0007).
  
  
  CONCLUSIONS
  These results support the hypothesis that poorly differentiated DCIS gradually evolve from well-differentiated DCIS by randomly acquiring genetic defects resulting in increasingly abnormal cellular features. This diversity is amplified by defects resulting in genetic instability (e.g., p53 mutation), and the alterations are propagated to IBC in a manner independent of progression to invasion.
authors.affiliation: Department of Pathology, Washington University School of Medicine, St Louis, MO 63110, USA. dcallred@path.wustl.edu
authors.forename: D Craig
authors.initials: DC
authors.lastname: Allred
authors.forename: Yun
authors.initials: Y
authors.lastname: Wu
authors.forename: Sufeng
authors.initials: S
authors.lastname: Mao
authors.forename: Iris D
authors.initials: ID
authors.lastname: Nagtegaal
authors.forename: Sangjun
authors.initials: S
authors.lastname: Lee
authors.forename: Charles M
authors.initials: CM
authors.lastname: Perou
authors.forename: Syed K
authors.initials: SK
authors.lastname: Mohsin
authors.forename: Peter
authors.initials: P
authors.lastname: O'Connell
authors.forename: Anna
authors.initials: A
authors.lastname: Tsimelzon
authors.forename: Dan
authors.initials: D
authors.lastname: Medina
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D018270:Carcinoma, Ductal, Breast / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D002285:Carcinoma, Intraductal, Noninfiltrating / Q000145:classification / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D018450:Disease Progression; D050990:GATA3 Transcription Factor / Q000378:metabolism; D018734:Genes, erbB-2; D016158:Genes, p53; D006801:Humans; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D014408:Biomarkers, Tumor; C413364:ERBIN protein, human; D050990:GATA3 Transcription Factor; C494749:GATA3 protein, human; D016159:Tumor Suppressor Protein p53