Integrative genomic characterization of oral squamous cell carcinoma identifies frequent somatic drivers.
Cancer Discov, 2013/7;3(7):770-81.
Pickering CR[1], Zhang J, Yoo SY, Bengtsson L, Moorthy S, Neskey DM, Zhao M, Ortega Alves MV, Chang K, Drummond J, Cortez E, Xie TX, Zhang D, Chung W, Issa JP, Zweidler-McKay PA, Wu X, El-Naggar AK, Weinstein JN, Wang J, Muzny DM, Gibbs RA, Wheeler DA, Myers JN, Frederick MJ
Affiliations
PMID: 23619168DOI: 10.1158/2159-8290.CD-12-0537
Impact factor: 38.272
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.
MeSH terms
Carcinoma, Squamous Cell; Caspase 8; Cell Line, Tumor; DNA Copy Number Variations; DNA Methylation; Gene Expression Regulation, Neoplastic; Genomics; Humans; Mouth Neoplasms; Point Mutation; Receptors, Notch
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