TY - JOUR
T1 - Integrative genomic characterization of oral squamous cell carcinoma identifies frequent somatic drivers
AU - Pickering, Curtis R.
AU - Zhang, Jiexin
AU - Yoo, Suk Young
AU - Bengtsson, Linnea
AU - Moorthy, Shhyam
AU - Neskey, David M.
AU - Zhao, Mei
AU - Ortega Alves, Marcus V.
AU - Chang, Kyle
AU - Drummond, Jennifer
AU - Cortez, Elsa
AU - Xie, Tong Xin
AU - Zhang, Di
AU - Chung, Woonbok
AU - Issa, Jean Pierre J.
AU - Zweidler-McKay, Patrick A.
AU - Wu, Xifeng
AU - El-Naggar, Adel K.
AU - Weinstein, John N.
AU - Wang, Jing
AU - Muzny, Donna M.
AU - Gibbs, Richard A.
AU - Wheeler, David A.
AU - Myers, Jeffrey N.
AU - Frederick, Mitchell J.
PY - 2013/7
Y1 - 2013/7
N2 - 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. SIGNIFICANCE: This is the first integrated genomic analysis of OSCC. Only through integrated multiplatform analysis was it possible to identify four key pathways. We also discovered a new disease subtype associated with CASP8 and HRAS mutation. Finally, many candidate targetable events were found and provide hope for future genomically driven therapeutic strategies.
AB - 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. SIGNIFICANCE: This is the first integrated genomic analysis of OSCC. Only through integrated multiplatform analysis was it possible to identify four key pathways. We also discovered a new disease subtype associated with CASP8 and HRAS mutation. Finally, many candidate targetable events were found and provide hope for future genomically driven therapeutic strategies.
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U2 - 10.1158/2159-8290.CD-12-0537
DO - 10.1158/2159-8290.CD-12-0537
M3 - Article
C2 - 23619168
AN - SCOPUS:84880281635
SN - 2159-8274
VL - 3
SP - 770
EP - 781
JO - Cancer discovery
JF - Cancer discovery
IS - 7
ER -