title: DNA copy number alterations in endobronchial squamous metaplastic lesions predict lung cancer.
abstract: BACKGROUND
  Autofluorescence bronchoscopy (AFB) is a valid strategy for detecting premalignant endobronchial lesions. However, no biomarker can reliably predict lung cancer risk of subjects with AFB-visualized premalignant lesions.
  
  
  OBJECTIVE
  The present study set out to identify AFB-visualized squamous metaplastic (SqM) lesions with malignant potential by DNA copy number profiling.
  
  
  METHODS
  Regular AFB examinations in 474 subjects at risk of lung cancer identified six subjects with SqM lesions at baseline, and carcinoma in situ or carcinoma (carcinoma in situ or greater) at the initial SqM site at follow-up bronchoscopy. These progressive SqM lesions were compared for immunostaining pattern and array comparative genomic hybridization-based chromosomal profiles with 23 SqM lesions of subjects who remained cancer-free. Specific DNA copy number alterations (CNAs) linked to cancer risk were identified and accuracy of CNAs to predict endobronchial cancer in this series was determined.
  
  
  RESULTS
  At baseline, p53, p63, and Ki-67 immunostaining were not predictive for a differential clinical outcome of SqM lesions. The mean number of CNAs in baseline SqM of cases was significantly higher compared with control subjects (P < 0.01). Chromosomal regions significantly more frequently altered in SqM of cases were 3p26.3-p11.1, 3q26.2-q29, 9p13.3-p13.2, and 17p13.3-p11.2 (family-wise error rate <0.10). CNAs were specifically detected at the site of future cancer. In cases, baseline-detected CNAs persisted in subsequent biopsies taken from the initial site, and levels increased toward cancer progression. In this series, a model based on CNAs at 3p26.3-p11.1, 3q26.2-29, and 6p25.3-24.3 predicted cancer with 97% accuracy.
  
  
  CONCLUSIONS
  The data suggest that the presence of specific CNAs in SqM lesions predict endobronchial cancer.
authors.affiliation: VU University Medical Center, Department of Pathology, De Boelelaan 1117, Amsterdam, The Netherlands.
authors.forename: Robert A A
authors.initials: RA
authors.lastname: van Boerdonk
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Sutedja
authors.forename: Peter J F
authors.initials: PJ
authors.lastname: Snijders
authors.forename: Emilie
authors.initials: E
authors.lastname: Reinen
authors.forename: Saskia M
authors.initials: SM
authors.lastname: Wilting
authors.forename: Mark A
authors.initials: MA
authors.lastname: van de Wiel
authors.forename: F Erik B J M
authors.initials: FE
authors.lastname: Thunnissen
authors.forename: Sylvia
authors.initials: S
authors.lastname: Duin
authors.forename: Clarissa
authors.initials: C
authors.lastname: Kooi
authors.forename: Bauke
authors.initials: B
authors.lastname: Ylstra
authors.forename: Chris J L M
authors.initials: CJ
authors.lastname: Meijer
authors.forename: Gerrit A
authors.initials: GA
authors.lastname: Meijer
authors.forename: Katrien
authors.initials: K
authors.lastname: Grünberg
authors.forename: Johannes M A
authors.initials: JM
authors.lastname: Daniels
authors.forename: Pieter E
authors.initials: PE
authors.lastname: Postmus
authors.forename: Egbert F
authors.initials: EF
authors.lastname: Smit
authors.forename: Daniëlle A M
authors.initials: DA
authors.lastname: Heideman
mesh_terms: D000368:Aged; D001706:Biopsy; D001999:Bronchoscopy; D002278:Carcinoma in Situ / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D016022:Case-Control Studies; D015331:Cohort Studies; D056915:DNA Copy Number Variations; D005260:Female; D005819:Genetic Markers; D006801:Humans; D008175:Lung Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D008297:Male; D008679:Metaplasia; D008875:Middle Aged; D012306:Risk
chemical_list: D005819:Genetic Markers