Integrative genomic characterization of oral squamous cell carcinoma identifies frequent somatic drivers.

 
TitleIntegrative genomic characterization of oral squamous cell carcinoma identifies frequent somatic drivers.
Publication TypeJournal Article
Year of Publication2013
AuthorsPickering, CR, Zhang, J, Yoo, SYoung, Bengtsson, L, Moorthy, S, Neskey, DM, Zhao, M, Alves, MVOrtega, Chang, K, Drummond, JA, Cortez, E, Xie, T-X, Zhang, D, Chung, W, Issa, J-PJ, Zweidler-McKay, PA, Wu, X, El-Naggar, AK, Weinstein, JN, Wang, J, Muzny, DM, Gibbs, RA, Wheeler, DA, Myers, JN, Frederick, MJ
JournalCancer Discov
Volume3
Issue7
Pagination770-81
Date Published2013 Jul
ISSN2159-8290
KeywordsCarcinoma, 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
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.

DOI10.1158/2159-8290.CD-12-0537
Alternate JournalCancer Discov
PubMed ID23619168
PubMed Central IDPMC3858325
Grant ListP30 CA016672 / CA / NCI NIH HHS / United States
P30CA0CA16672 / CA / NCI NIH HHS / United States
P50 CA097007 / CA / NCI NIH HHS / United States
P50CA097007 / CA / NCI NIH HHS / United States
RC2 DE020958 / DE / NIDCR NIH HHS / United States
RC2DE020958 / DE / NIDCR NIH HHS / United States
U54 HG003273 / HG / NHGRI NIH HHS / United States