Loss-of-function Mutations in Notch Receptors in Cutaneous and Lung Squamous Cell Carcinoma

Proc Natl Acad Sci U S A. 2011 Oct 25;108(43):17761-6. doi: 10.1073/pnas.1114669108. Epub 2011 Oct 17.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Base Sequence
  • Carcinoma, Squamous Cell / genetics*
  • Cell Communication / genetics*
  • Codon, Nonsense / genetics
  • Electrophoretic Mobility Shift Assay
  • Humans
  • Lod Score
  • Lung Neoplasms / genetics*
  • Molecular Sequence Data
  • Receptor, Notch1 / genetics*
  • Receptor, Notch2 / genetics*
  • Sequence Analysis, DNA
  • Signal Transduction / genetics*
  • Skin Neoplasms / genetics*

Substances

  • Codon, Nonsense
  • NOTCH1 protein, human
  • NOTCH2 protein, human
  • Receptor, Notch1
  • Receptor, Notch2