The survival of patients with oral squamous cell carcinoma (OSCC) has not changed significantly in several decades, leading clinicians and investigators to search for promising molecular targets. To this end, we performed comprehensive genomic analysis of gene expression, copy number, methylation and point mutations in OSCC. Integrated analysis revealed more somatic events than previously reported, identifying four major driver pathways (mitogenic signaling, Notch, cell cycle, TP53) and two additional key genes (FAT1, CASP8). The Notch pathway was defective in 66% of patients, and in follow-up studies of mechanism, functional NOTCH1 signaling inhibited proliferation of OSCC cell lines. Frequent mutation of CASP8 defines a new molecular subtype of OSCC with few copy number changes. Although genomic alterations are dominated by loss of tumor suppressor genes, 80% of patients harbored at least one genomic alteration in a targetable gene, suggesting that novel approaches to treatment may be possible for this debilitating disease.
Purpose
Epidemiological studies have identified an increasing incidence of squamous cell carcinoma of the oral tongue (SCCOT) in younger patients.
Experimental Design
DNA isolated from tongue tumors of young (<45 yrs, non-smokers) and old (>45 yrs) patients at was subjected to whole-exome sequencing and copy number analysis. These data were compared to data from similar patients in the The Cancer Genome Atlas (TCGA) project.
Results
In this study, we found that gene-specific mutation and copy number alteration frequencies were similar between young and old SCCOT patients in two independent cohorts. Likewise, the types of base changes observed in the young cohort were similar to those in the old cohort even though they differed in smoking history. TCGA data also demonstrate that the genomic effects of smoking are tumor-site specific, and we find that smoking has only a minor impact on the types of mutations observed in SCCOT.
Conclusions
Overall, tumors from young SCCOT patients appear genomically similar to those of older SCCOT patients, and the cause for the increasing incidence of young SCCOT remains unknown. These data indicate that the functional impact of smoking on carcinogenesis in SCCOT is still poorly understood.
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