title: Cell migration leads to spatially distinct but clonally related airway cancer precursors.
abstract: BACKGROUND
  Squamous cell carcinoma of the lung is a common cancer with 95% mortality at 5 years. These cancers arise from preinvasive lesions, which have a natural history of development progressing through increasing severity of dysplasia to carcinoma in situ (CIS), and in some cases, ending in transformation to invasive carcinoma. Synchronous preinvasive lesions identified at autopsy have been previously shown to be clonally related.
  
  
  METHODS
  Using autofluorescence bronchoscopy that allows visual observation of preinvasive lesions within the upper airways, together with molecular profiling of biopsies using gene sequencing and loss-of-heterozygosity analysis from both preinvasive lesions and from intervening normal tissue, we have monitored individual lesions longitudinally and documented their visual, histological and molecular relationship.
  
  
  RESULTS
  We demonstrate that rather than forming a contiguous field of abnormal tissue, clonal CIS lesions can develop at multiple anatomically discrete sites over time. Further, we demonstrate that patients with CIS in the trachea have invariably had previous lesions that have migrated proximally, and in one case, into the other lung over a period of 12 years.
  
  
  CONCLUSIONS
  Molecular information from these unique biopsies provides for the first time evidence that field cancerisation of the upper airways can occur through cell migration rather than via local contiguous cellular expansion as previously thought. Our findings urge a clinical strategy of ablating high-grade premalignant airway lesions with subsequent attentive surveillance for recurrence in the bronchial tree.
authors.affiliation: Lungs for Living Research Centre, UCL Respiratory, University College London, London, UK.
authors.forename: Christodoulos P
authors.initials: CP
authors.lastname: Pipinikas
authors.affiliation: Lungs for Living Research Centre, UCL Respiratory, University College London, London, UK Department of Respiratory Medicine, University of Thessaly School of Medicine, Larissa, Greece.
authors.forename: Theodoros S
authors.initials: TS
authors.lastname: Kiropoulos
authors.affiliation: Lungs for Living Research Centre, UCL Respiratory, University College London, London, UK.
authors.forename: Vitor H
authors.initials: VH
authors.lastname: Teixeira
authors.affiliation: Lungs for Living Research Centre, UCL Respiratory, University College London, London, UK.
authors.forename: James M
authors.initials: JM
authors.lastname: Brown
authors.affiliation: Lungs for Living Research Centre, UCL Respiratory, University College London, London, UK.
authors.forename: Aikaterini
authors.initials: A
authors.lastname: Varanou
authors.affiliation: Department of Pathology, University College London, London, UK.
authors.forename: Mary
authors.initials: M
authors.lastname: Falzon
authors.affiliation: Department of Pathology, University College London, London, UK.
authors.forename: Arrigo
authors.initials: A
authors.lastname: Capitanio
authors.affiliation: Lungs for Living Research Centre, UCL Respiratory, University College London, London, UK.
authors.forename: Steven E
authors.initials: SE
authors.lastname: Bottoms
authors.affiliation: Department of Thoracic Medicine, University College London Hospital, London, UK.
authors.forename: Bernadette
authors.initials: B
authors.lastname: Carroll
authors.affiliation: Lungs for Living Research Centre, UCL Respiratory, University College London, London, UK Department of Thoracic Medicine, University College London Hospital, London, UK.
authors.forename: Neal
authors.initials: N
authors.lastname: Navani
authors.affiliation: Department of Biochemistry, University of Cambridge, Cambridge, UK Department of Asthma, Allergy and Respiratory Science, King's College London, London, UK.
authors.forename: Frank
authors.initials: F
authors.lastname: McCaughan
authors.affiliation: Department of Thoracic Medicine, University College London Hospital, London, UK.
authors.forename: Jeremy P
authors.initials: JP
authors.lastname: George
authors.affiliation: Lungs for Living Research Centre, UCL Respiratory, University College London, London, UK.
authors.forename: Adam
authors.initials: A
authors.lastname: Giangreco
authors.affiliation: Histopathology Laboratory, Cancer Research UK London Research Institute, London, UK Centre for Digestive Diseases, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Wright
authors.affiliation: Histopathology Laboratory, Cancer Research UK London Research Institute, London, UK Centre for Digestive Diseases, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors.forename: Stuart A C
authors.initials: SA
authors.lastname: McDonald
authors.affiliation: Histopathology Laboratory, Cancer Research UK London Research Institute, London, UK Centre for Evolution and Cancer, UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, California, USA.
authors.forename: Trevor A
authors.initials: TA
authors.lastname: Graham
authors.affiliation: Lungs for Living Research Centre, UCL Respiratory, University College London, London, UK.
authors.forename: Sam M
authors.initials: SM
authors.lastname: Janes
mesh_terms: D000328:Adult; D002278:Carcinoma in Situ / Q000235:genetics / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000473:pathology; D002465:Cell Movement; D016158:Genes, p53; D006801:Humans; D019656:Loss of Heterozygosity; D008175:Lung Neoplasms / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology; D011230:Precancerous Conditions / Q000235:genetics / Q000473:pathology; D014134:Tracheal Neoplasms / Q000235:genetics / Q000473:pathology
keywords: Airway Epithelium; Lung Cancer