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Genetic Progression and Clonal Relationship of Recurrent Premalignant Head and Neck Lesions

Departments of Otolaryngology-Head and Neck Surgery [J. C., W. H. W., G. M., W. K., D. S.] and Pathology [W. H. W., R. C.], Johns Hopkins Hospital, Baltimore, Maryland 21204

We constructed a preliminary genetic progression model for head and neck squamous cell carcinoma (HNSC) based on the frequency of genetic alterations in preneoplastic and neoplastic lesions from single biopsy specimens. To firmly establish the temporal order of established genetic events in HNSC, we sampled serial biopsies from five patients with recurrent premalignant lesions 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 regions 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 heterozygosity) of identical alleles at multiple loci with identical boundaries between areas of LOH and retention of heterozygosity, indicating a common clonal origin for each set. Three patients demonstrated genetic progression (new regions of LOH) over time correlating with histopathological progression, one patient demonstrated lack of genetic progression associated with unchanged histopathological morphology, and one patient demonstrated histopathological progression without detection of a corresponding genetic progression event. For one of these patients with a laryngeal tumor, at least four separate steps in progression to malignancy could be determined, accompanied by spatial expansion of an increasingly altered clonal population from the ipsilateral to the contralateral side, ultimately resulting in a malignancy. Microsatellite-based genetic analysis of recurrent premalignant lesions indicates that these lesions arise from a common clonal progenitor, followed by outgrowth of clonal populations associated with progressive genetic alterations and phenotypic progression to malignancy.

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