title: Genomic evidence of pre-invasive clonal expansion, dispersal and progression in bronchial dysplasia.
abstract: The term 'field cancerization' is used to describe an epithelial surface that has a propensity to develop cancerous lesions, and in the case of the aerodigestive tract this is often as a result of chronic exposure to carcinogens in cigarette smoke 1, 2. The clinical endpoint is the development of multiple tumours, either simultaneously or sequentially in the same epithelial surface. The mechanisms underlying this process remain unclear; one possible explanation is that the epithelium is colonized by a clonal population of cells that are at increased risk of progression to cancer. We now address this possibility in a short case series, using individual genomic events as molecular biomarkers of clonality. In squamous lung cancer the most common genomic aberration is 3q amplification. We use a digital PCR technique to assess the clonal relationships between multiple biopsies in a longitudinal bronchoscopic study, using amplicon boundaries as markers of clonality. We demonstrate that clonality can readily be defined by these analyses and confirm that field cancerization occurs at a pre-invasive stage and that pre-invasive lesions and subsequent cancers are clonally related. We show that while the amplicon boundaries can be shared between different biopsies, the degree of 3q amplification and the internal structure of the 3q amplicon varies from lesion to lesion. Finally, in this small cohort, the degree of 3q amplification corresponds to clinical progression.
authors.affiliation: MRC Laboratory of Molecular Biology, Cambridge, UK. frankmc@mrc-lmb.cam.ac.uk
authors.forename: Frank
authors.initials: F
authors.lastname: McCaughan
authors.forename: Christodoulos P
authors.initials: CP
authors.lastname: Pipinikas
authors.forename: Sam M
authors.initials: SM
authors.lastname: Janes
authors.forename: P Jeremy
authors.initials: PJ
authors.lastname: George
authors.forename: Pamela H
authors.initials: PH
authors.lastname: Rabbitts
authors.forename: Paul H
authors.initials: PH
authors.lastname: Dear
mesh_terms: D000328:Adult; D001706:Biopsy; D001980:Bronchi / Q000473:pathology*; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000473:pathology*; D018450:Disease Progression; D005260:Female; D023281:Genomics / Q000379:methods; D006801:Humans; D008137:Longitudinal Studies; D008175:Lung Neoplasms / Q000235:genetics / Q000473:pathology*; D042282:Microdissection / Q000379:methods; D014411:Neoplastic Stem Cells / Q000473:pathology*; D011230:Precancerous Conditions / Q000235:genetics / Q000473:pathology*