Genetic progression and clonal relationship of recurrent premalignant headand neck lesions

We constructed a preliminary genetic progression model for head and neck sq uamous cell carcinoma (HNSC) based on the frequency of genetic alterations in preneoplastic and neoplastic lesions from single biopsy specimens. To fi rmly establish the temporal order of established genetic events in HNSC, we sampled serial biopsies from five patients with recurrent premalignant les ions at a single anatomic site over a period of time (1 month to 144 months ). These lesions were examined by microsatellite analysis of the minimal re gions of loss on the 10 most frequently lost chromosomal arms in HNSC. Each set of serial biopsies from all five patients demonstrated LOH (loss of he terozygosity) of identical alleles at multiple loci with identical boundari es between areas of LOH and retention of heterozygosity, indicating a commo n clonal origin for each set. Three patients demonstrated genetic progressi on (new regions of LOH) over time correlating with histopathological progre ssion, one patient demonstrated lack of genetic progression associated,vith unchanged histopathological morphology, and one patient demonstrated histo pathological progression without detection of a corresponding genetic progr ession event. For one of these patients with a laryngeal tumor, at least fo ur separate steps in progression to malignancy could be determined, accompa nied by spatial expansion of an increasingly altered clonal population from the ipsilateral to the contralateral side, ultimately resulting in a malig nancy. Microsatellite-based genetic analysis of recurrent premalignant lesi ons indicates that these lesions arise from a common clonal progenitor, fol lowed by outgrowth of clonal populations associated with progressive geneti c alterations and phenotypic progression to malignancy.