Activation of the NOTCH pathway in head and neck cancer

Wenyue Sun, Daria A. Gaykalova, Michael F. Ochs, Elizabeth Mambo, Demetri Arnaoutakis, Yan Liu, Myriam Loyo, Nishant Agrawal, Jason Howard, Ryan Li, Sun Ahn, Elana Fertig, David Sidransky, Jeffery Houghton, Kalyan Buddavarapu, Tiffany Sanford, Ashish Choudhary, Will Darden, Alex Adai, Gary LathamJustin Bishop, Rajni Sharma, William H. Westra, Patrick Hennessey, Christine H. Chung, Joseph A. Califano

Research output: Contribution to journalArticle

123 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1091-1104
Number of pages14
JournalCancer research
Volume74
Issue number4
DOIs
StatePublished - Feb 15 2014

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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  • Cite this

    Sun, W., Gaykalova, D. A., Ochs, M. F., Mambo, E., Arnaoutakis, D., Liu, Y., Loyo, M., Agrawal, N., Howard, J., Li, R., Ahn, S., Fertig, E., Sidransky, D., Houghton, J., Buddavarapu, K., Sanford, T., Choudhary, A., Darden, W., Adai, A., ... Califano, J. A. (2014). Activation of the NOTCH pathway in head and neck cancer. Cancer research, 74(4), 1091-1104. https://doi.org/10.1158/0008-5472.CAN-13-1259