Loss-of-function mutations in Notch receptors in cutaneous and lung squamous cell carcinoma

Nicholas J. Wang, Zachary Sanborn, Kelly L. Arnett, Laura J. Bayston, Wilson Liao, Charlotte M. Proby, Irene M. Leigh, Eric A. Collisson, Patricia B. Gordon, Lakshmi Jakkula, Sally Pennypacker, Yong Zou, Mimansa Sharma, Jeffrey P. North, Swapna S. Vemula, Theodora M. Mauro, Isaac M. Neuhaus, Philip E. LeBoit, Joe S. Hur, Kyunghee ParkNam Huh, Pui Yan Kwok, Sarah T. Arron, Pierre P. Massion, Allen E. Bale, David Haussler, James E. Cleaver, Joe W. Gray, Paul T. Spellman, Andrew P. South, Jon C. Aster, Stephen C. Blacklow, Raymond J. Cho

Research output: Contribution to journalArticle

260 Scopus citations

Abstract

Squamous cell carcinomas (SCCs) are one of the most frequent forms of human malignancy, but, other than TP53 mutations, few causative somatic aberrations have been identified. We identified NOTCH1 or NOTCH2 mutations in ∼75% of cutaneous SCCs and in a lesser fraction of lung SCCs, defining a spectrum for the most prevalent tumor suppressor specific to these epithelial malignancies. Notch receptors normally transduce signals in response to ligands on neighboring cells, regulating metazoan lineage selection and developmental patterning. Our findings therefore illustrate a central role for disruption of microenvironmental communication in cancer progression. NOTCH aberrations include frameshift and nonsense mutations leading to receptor truncations as well as point substitutions in key functional domains that abrogate signaling in cell-based assays. Oncogenic gain-of-function mutations in NOTCH1 commonly occur in human T-cell lymphoblastic leukemia/lymphoma and B-cell chronic lymphocytic leukemia. The bifunctional role of Notch in human cancer thus emphasizes the context dependency of signaling outcomes and suggests that targeted inhibition of the Notch pathway may induce squamous epithelial malignancies.

Original languageEnglish (US)
Pages (from-to)17761-17766
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number43
DOIs
StatePublished - Oct 25 2011

Keywords

  • Cancer genetics
  • Cellular signaling
  • Genomic

ASJC Scopus subject areas

  • General

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    Wang, N. J., Sanborn, Z., Arnett, K. L., Bayston, L. J., Liao, W., Proby, C. M., Leigh, I. M., Collisson, E. A., Gordon, P. B., Jakkula, L., Pennypacker, S., Zou, Y., Sharma, M., North, J. P., Vemula, S. S., Mauro, T. M., Neuhaus, I. M., LeBoit, P. E., Hur, J. S., ... Cho, R. J. (2011). Loss-of-function mutations in Notch receptors in cutaneous and lung squamous cell carcinoma. Proceedings of the National Academy of Sciences of the United States of America, 108(43), 17761-17766. https://doi.org/10.1073/pnas.1114669108