Abstract
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 conducted 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, and 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 caspase-8 (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 subset of head and neck cancers.
Highlights
Head and neck squamous cell carcinoma (HNSCC) includes a diverse group of tumors from the upper aerodigestive tract [1]
Genome-wide copy number alterations (CNA) as well as tumor purity and tumor ploidy were computed from high-quality SNP arrays from 38 Oral squamous cell carcinoma (OSCC) patients (Supplementary Figure S1A and Tables S1–S2)
Together with the high level of polyploidy, those CNA findings suggest that genomic instability is a dominant feature of OSCC
Summary
Head and neck squamous cell carcinoma (HNSCC) includes a diverse group of tumors from the upper aerodigestive tract [1]. Oral squamous cell carcinoma (OSCC), a subset of the disease, has a five-year survival rate of only about 50% [1]. TP53 was the only known recurrent mutation, with frequencies ranging from 60 to 80%. We and others recently showed NOTCH1 mutations in 15% of patients by whole exome sequencing [2, 3], thereby opening new avenues of investigation. The Notch pathway in cancer was first recognized in hematopoietic malignancies as oncogenic [4], but in OSCC, NOTCH1 mutations are believed to be tumor-suppressive [2, 3, 5]
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