title: Molecular differences between ductal carcinoma in situ and adjacent invasive breast carcinoma: a multiplex ligation-dependent probe amplification study.
abstract: BACKGROUND
  Ductal carcinoma in situ (DCIS) accounts for approximately 20% of mammographically detected breast cancers. Although DCIS is generally highly curable, some women with DCIS will develop life-threatening invasive breast cancer, but the determinants of progression to infiltrating ductal cancer (IDC) are largely unknown.
  
  
  METHODS
  In the current study, we used multiplex ligation-dependent probe amplification (MLPA), a multiplex PCR-based test, to compare copy numbers of 21 breast cancer related genes between laser-microdissected DCIS and adjacent IDC lesions in 39 patients. Genes included in this study were ESR1, EGFR, FGFR1, ADAM9, IKBKB, PRDM14, MTDH, MYC, CCND1, EMSY, CDH1, TRAF4, CPD, MED1, HER2, CDC6, TOP2A, MAPT, BIRC5, CCNE1 and AURKA.
  
  
  RESULTS
  There were no significant differences in copy number for the 21 genes between DCIS and adjacent IDC. Low/intermediate-grade DCIS showed on average 6 gains/amplifications versus 8 in high-grade DCIS (p = 0.158). Furthermore, alterations of AURKA and CCNE1 were exclusively found in high-grade DCIS, and HER2, PRDM14 and EMSY amplification was more frequent in high-grade DCIS than in low/intermediate-grade DCIS. In contrast, the average number of alterations in low/intermediate and high grade IDC was similar, and although EGFR alterations were exclusively found in high grade IDC compared to low/intermediate-grade IDC, there were generally fewer differences between low/intermediate-grade and high-grade IDC than between low/intermediate-grade and high-grade DCIS.
  
  
  CONCLUSIONS
  In conclusion, there were no significant differences in copy number for 21 breast cancer related genes between DCIS and adjacent IDC, indicating that DCIS is genetically as advanced as its invasive counterpart. However, high grade DCIS showed more copy number changes than low/intermediate grade DCIS with specifically involved genes, supporting a model in which different histological grades of DCIS are associated with distinct genomic changes that progress to IDC in different routes. These high grade DCIS specific genes may be potential targets for treatment and/or predict progression.
authors.affiliation: Department of Pathology, University Medical Center Utrecht, Heidelberglaan 100, PO Box 85500, 3508 GA, Utrecht, The Netherlands. cmoelans@umcutrecht.nl
authors.forename: Cathy B
authors.initials: CB
authors.lastname: Moelans
authors.forename: Roel A
authors.initials: RA
authors.lastname: de Wegers
authors.forename: Hanneke N
authors.initials: HN
authors.lastname: Monsuurs
authors.forename: Anoek H J
authors.initials: AH
authors.lastname: Maess
authors.forename: Paul J
authors.initials: PJ
authors.lastname: van Diest