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

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, a...

Full description

Saved in:
Bibliographic Details
Published in:Cancer discovery 2013-07, Vol.3 (7), p.770-781
Main Authors: Pickering, Curtis R, Zhang, Jiexin, Yoo, Suk Young, Bengtsson, Linnea, Moorthy, Shhyam, Neskey, David M, Zhao, Mei, Ortega Alves, Marcus V, Chang, Kyle, Drummond, Jennifer, Cortez, Elsa, Xie, Tong-Xin, Zhang, Di, Chung, Woonbok, Issa, Jean-Pierre J, Zweidler-McKay, Patrick A, Wu, Xifeng, El-Naggar, Adel K, Weinstein, John N, Wang, Jing, Muzny, Donna M, Gibbs, Richard A, Wheeler, David A, Myers, Jeffrey N, Frederick, Mitchell J
Format: Article
Language:English
Subjects:
Carcinoma, Squamous Cell - genetics
Carcinoma, Squamous Cell - pathology
Caspase 8 - genetics
Caspase 8 - metabolism
Cell Line, Tumor
DNA Copy Number Variations - genetics
DNA Methylation - genetics
Gene Expression Regulation, Neoplastic - genetics
Genomics
Humans
Mouth Neoplasms - genetics
Mouth Neoplasms - pathology
Point Mutation - genetics
Receptors, Notch - genetics
Receptors, Notch - metabolism
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:2159-8274
2159-8290
DOI:10.1158/2159-8290.cd-12-0537