title: Activation of the NOTCH pathway in head and neck cancer.
abstract: NOTCH1 mutations have been reported to occur in 10% to 15% of head and neck squamous cell carcinomas (HNSCC). To determine the significance of these mutations, we embarked upon a comprehensive study of NOTCH signaling in a cohort of 44 HNSCC tumors and 25 normal mucosal samples through a set of expression, copy number, methylation, and mutation analyses. Copy number increases were identified in NOTCH pathway genes, including the NOTCH ligand JAG1. Gene set analysis defined a differential expression of the NOTCH signaling pathway in HNSCC relative to normal tissues. Analysis of individual pathway-related genes revealed overexpression of ligands JAG1 and JAG2 and receptor NOTCH3. In 32% of the HNSCC examined, activation of the downstream NOTCH effectors HES1/HEY1 was documented. Notably, exomic sequencing identified 5 novel inactivating NOTCH1 mutations in 4 of the 37 tumors analyzed, with none of these tumors exhibiting HES1/HEY1 overexpression. Our results revealed a bimodal pattern of NOTCH pathway alterations in HNSCC, with a smaller subset exhibiting inactivating NOTCH1 receptor mutations but a larger subset exhibiting other NOTCH1 pathway alterations, including increases in expression or gene copy number of the receptor or ligands as well as downstream pathway activation. Our results imply that therapies that target the NOTCH pathway may be more widely suitable for HNSCC treatment than appreciated currently.
authors.affiliation: Authors' Affiliations: Departments of Otolaryngology-Head and Neck Surgery, Oncology and Health Science Informatics, Surgery, Oncology, and Pathology, Johns Hopkins Medical Institutions; Milton J. Dance Head and Neck Center, Greater Baltimore Medical Center, Baltimore, Maryland; and Asuragen Inc., Austin, Texas.
authors.forename: Wenyue
authors.initials: W
authors.lastname: Sun
authors.forename: Daria A
authors.initials: DA
authors.lastname: Gaykalova
authors.forename: Michael F
authors.initials: MF
authors.lastname: Ochs
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Mambo
authors.forename: Demetri
authors.initials: D
authors.lastname: Arnaoutakis
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.forename: Myriam
authors.initials: M
authors.lastname: Loyo
authors.forename: Nishant
authors.initials: N
authors.lastname: Agrawal
authors.forename: Jason
authors.initials: J
authors.lastname: Howard
authors.forename: Ryan
authors.initials: R
authors.lastname: Li
authors.forename: Sun
authors.initials: S
authors.lastname: Ahn
authors.forename: Elana
authors.initials: E
authors.lastname: Fertig
authors.forename: David
authors.initials: D
authors.lastname: Sidransky
authors.forename: Jeffery
authors.initials: J
authors.lastname: Houghton
authors.forename: Kalyan
authors.initials: K
authors.lastname: Buddavarapu
authors.forename: Tiffany
authors.initials: T
authors.lastname: Sanford
authors.forename: Ashish
authors.initials: A
authors.lastname: Choudhary
authors.forename: Will
authors.initials: W
authors.lastname: Darden
authors.forename: Alex
authors.initials: A
authors.lastname: Adai
authors.forename: Gary
authors.initials: G
authors.lastname: Latham
authors.forename: Justin
authors.initials: J
authors.lastname: Bishop
authors.forename: Rajni
authors.initials: R
authors.lastname: Sharma
authors.forename: William H
authors.initials: WH
authors.lastname: Westra
authors.forename: Patrick
authors.initials: P
authors.lastname: Hennessey
authors.forename: Christine H
authors.initials: CH
authors.lastname: Chung
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Califano
mesh_terms: D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D019175:DNA Methylation / Q000502:physiology; D018628:Gene Dosage; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006258:Head and Neck Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D006801:Humans; D046228:Microarray Analysis; D009092:Mucous Membrane / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D011401:Promoter Regions, Genetic; D051881:Receptor, Notch1 / Q000235:genetics*; D015398:Signal Transduction / Q000502:physiology; D000077195:Squamous Cell Carcinoma of Head and Neck; D015533:Transcriptional Activation / Q000502:physiology; D014407:Tumor Cells, Cultured
chemical_list: D051881:Receptor, Notch1