title: Nuclear morphometry as a biomarker for bronchial intraepithelial neoplasia: correlation with genetic damage and cancer development.
abstract: BACKGROUND
  Bronchial carcinomas are preceded by epithelial morphologic changes. The variation in interpretation of these grades of intraepithelial neoplasia makes it difficult to determine its natural history and utility of histopathology as a surrogate endpoint biomarker. The objective of this study was to quantitate morphologic changes of intraepitherlial neoplasia and validate its utility through correlation with histopathology, allelic loss, and cancer development.
  
  
  METHODS
  Quantitative nuclear morphometry was performed on 47 normal bronchial biopsies and 28 invasive cancer to generate a morphometry index (MI) that was applied to 1,096 bronchial biopsies from 230 volunteers who were current smokers (> or =25 pack-years) and 30 patients who had cancer. In a subset of 631 biopsies, MI was correlated with frequency of loss of heterozygosity at nine chromosomal regions (14 polymorphic markers).
  
  
  RESULTS
  A significant correlation was found between MI and allelic loss in six of nine chromosomal regions. As part of patient long-term follow-up, 12 sites that progressed to cancer were identified and had significantly increased MIs relative to nonprogressing sites. Significant overlap in the MIs was found between most grades of intraepithelial neoplasia.
  
  
  CONCLUSIONS
  In chemoprevention trials, nuclear morphometry can supplement histopathology as a Surrogate Endpont Biomarker (SEB) because it is quantitative, collelates well with genetic damage, and may predict cancer development.
authors.affiliation: Department of Cancer Imaging, Vancouver, British Columbia, Canada.
authors.forename: Martial
authors.initials: M
authors.lastname: Guillaud
authors.forename: Jean C
authors.initials: JC
authors.lastname: le Riche
authors.forename: Chris
authors.initials: C
authors.lastname: Dawe
authors.forename: Jagoda
authors.initials: J
authors.lastname: Korbelik
authors.forename: Andy
authors.initials: A
authors.lastname: Coldman
authors.forename: Ignacio I
authors.initials: II
authors.lastname: Wistuba
authors.forename: In-Won
authors.initials: IW
authors.lastname: Park
authors.forename: Adi
authors.initials: A
authors.lastname: Gazdar
authors.forename: Stephen
authors.initials: S
authors.lastname: Lam
authors.forename: Calum E
authors.initials: CE
authors.lastname: MacAulay
mesh_terms: D001706:Biopsy; D001984:Bronchial Neoplasms / Q000473:pathology*; D002278:Carcinoma in Situ / Q000473:pathology*; D002467:Cell Nucleus / Q000473:pathology*; D005260:Female; D006801:Humans; D019656:Loss of Heterozygosity; D008297:Male; D008875:Middle Aged; D012907:Smoking