Loss-of-Function Notch Receptor Mutations in Cutaneous and Lung Squamous Cell Carcinoma
Journal
P NATL ACAD SCI USA (PNAS)
Date
2011.10.25
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 loss-
of-function NOTCH1 or NOTCH2 mutations in approximately 75％ of cutaneous SCCs (cSCCs) 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.