Context: Carcinogens associated with head and neck squamous cell carcinoma (SCC) genesis should inflict genomic alterations not only on the epithelium but also the mesenchyme of the aerodigestive tract. Therefore, the apparently nonmalignant stroma surrounding the tumor epithelium can acquire genomic alterations and contribute to cancer initiation and progression. Objectives: To determine compartment-specific loci of loss of heterozygosity or allelic imbalance (LOH/AI) and to identify which genomic alterations restricted to the stroma cell population contribute to aggressiveness of head and neck SCC disease. Design, Setting, and Patients: Tumor epithelium and surrounding stroma were isolated from 122 US patients with oral cavity and oropharyngeal or hypopharyngeal SCC and subjected to whole-genome LOH/AI analysis using 366 microsatellite markers. Samples, collected between 2001 and 2004, were pulled and transferred in batches of 10 to 30 between 2002 and 2005. Laser capture microdissection DNA extraction and technical genotyping occurred on a rolling model between 2002 and November 2005. Main Outcome Measures: Compartment-specific frequency and distribution of LOH/AI were determined, and hot spots of genomic alterations identified. Compartment-specific LOH/AI events were correlated with presenting clinicopathologic characteristics. Results: Tumor-associated stroma of head and neck SCC from smokers were found to have a high degree of genomic alterations. A correlation between tumor aggressiveness could be found for a specific set of 5 loci. Three stroma-specific loci (D4S2417, D3S360, and D19555) were associated with tumor size (pT) and regional nodal metastases (pN). Furthermore, 2 epithelial-specific LOH/AI hot spots were positively correlated with pN status and clinical stage. Conclusions: Stroma-specific genetic alterations are associated with smoking-related head and neck SCC genesis. These findings suggest novel prognostic or diagnostic biomarkers and identify potential new molecular targets for therapeutic and preventive intervention.
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