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

Wang NJ, Sanborn Z, Arnett KL, Bayston LJ, Liao W, Proby CM, Leigh IM, Collisson EA, Gordon PB, Jakkula L, Pennypacker S, Zou Y, Sharma M, North JP, Vemula SS, Mauro TM, Neuhaus IM, Leboit PE, Hur JS, Park K, Huh N, Kwok PY, Arron ST, Massion PP, Bale AE, Haussler D, Cleaver JE, Gray JW, Spellman PT, South AP, Aster JC, Blacklow SC, Cho RJ
Proc Natl Acad Sci U S A. 2011 108 (43): 17761-6

PMID: 22006338 · PMCID: PMC3203814 · DOI:10.1073/pnas.1114669108

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.

MeSH Terms (14)

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

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