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Integrative Genomic Characterization of Oral Squamous Cell Carcinoma Identifies Frequent Somatic Drivers

2013; American Association for Cancer Research; Volume: 3; Issue: 7 Linguagem: Inglês

10.1158/2159-8290.cd-12-0537

2159-8290

Curtis R. Pickering, Jiexin Zhang, Suk Young Yoo, Linnéa Bengtsson, Shhyam Moorthy, David M. Neskey, Mei Zhao, Marcus V. Ortega Alves, Kyle Chang, Jennifer Drummond, Elsa Cortez, Tong-Xin Xie, Di Zhang, Woonbok Chung, Jean‐Pierre J. Issa, Patrick A. Zweidler‐McKay, Xifeng Wu, Adel K. El‐Naggar, John N. Weinstein, Jing Wang, Donna M. Muzny, Richard A. Gibbs, David A. Wheeler, Jeffrey N. Myers, Mitchell J. Frederick,

RNA modifications and cancer

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.