title: Integrative genomic characterization of oral squamous cell carcinoma identifies frequent somatic drivers.
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.
authors.affiliation: Departments of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Temple University School of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Curtis R
authors.initials: CR
authors.lastname: Pickering
authors.forename: Jiexin
authors.initials: J
authors.lastname: Zhang
authors.forename: Suk Young
authors.initials: SY
authors.lastname: Yoo
authors.forename: Linnea
authors.initials: L
authors.lastname: Bengtsson
authors.forename: Shhyam
authors.initials: S
authors.lastname: Moorthy
authors.forename: David M
authors.initials: DM
authors.lastname: Neskey
authors.forename: Mei
authors.initials: M
authors.lastname: Zhao
authors.forename: Marcus V
authors.initials: MV
authors.lastname: Ortega Alves
authors.forename: Kyle
authors.initials: K
authors.lastname: Chang
authors.forename: Jennifer
authors.initials: J
authors.lastname: Drummond
authors.forename: Elsa
authors.initials: E
authors.lastname: Cortez
authors.forename: Tong-Xin
authors.initials: TX
authors.lastname: Xie
authors.forename: Di
authors.initials: D
authors.lastname: Zhang
authors.forename: Woonbok
authors.initials: W
authors.lastname: Chung
authors.forename: Jean-Pierre J
authors.initials: JP
authors.lastname: Issa
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Zweidler-McKay
authors.forename: Xifeng
authors.initials: X
authors.lastname: Wu
authors.forename: Adel K
authors.initials: AK
authors.lastname: El-Naggar
authors.forename: John N
authors.initials: JN
authors.lastname: Weinstein
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.forename: Donna M
authors.initials: DM
authors.lastname: Muzny
authors.forename: Richard A
authors.initials: RA
authors.lastname: Gibbs
authors.forename: David A
authors.initials: DA
authors.lastname: Wheeler
authors.forename: Jeffrey N
authors.initials: JN
authors.lastname: Myers
authors.forename: Mitchell J
authors.initials: MJ
authors.lastname: Frederick
mesh_terms: D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000473:pathology; D053181:Caspase 8 / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D056915:DNA Copy Number Variations / Q000235:genetics*; D019175:DNA Methylation / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D023281:Genomics; D006801:Humans; D009062:Mouth Neoplasms / Q000235:genetics* / Q000473:pathology; D017354:Point Mutation / Q000235:genetics; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism
chemical_list: D051880:Receptors, Notch; D053181:Caspase 8