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Published on: January 12, 2020
Loss-of-function mutations in Notch receptors in cutaneous and lung squamous cell carcinoma
Nicholas J Wang1, Zachary Sanborn, Kelly L Arnett
1Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
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.
Insights
NOTCH1 and NOTCH2 mutations are prevalent in squamous cell carcinomas (SCCs), acting as key tumor suppressors. Disrupted Notch signaling highlights the role of microenvironmental communication in epithelial cancer progression.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Squamous cell carcinomas (SCCs) are common human malignancies with limited identified causative somatic aberrations beyond TP53 mutations.
- The Notch signaling pathway plays a crucial role in cell communication, lineage selection, and developmental patterning.
Purpose of the Study:
- To identify prevalent somatic aberrations in cutaneous and lung squamous cell carcinomas.
- To investigate the role of NOTCH1 and NOTCH2 mutations in SCC development and progression.
Main Methods:
- Genomic analysis of cutaneous and lung SCC samples to identify NOTCH1 and NOTCH2 mutations.
- Functional assays to assess the impact of identified mutations on Notch receptor signaling.
Main Results:
- NOTCH1 or NOTCH2 mutations were identified in approximately 75% of cutaneous SCCs and a smaller fraction of lung SCCs.
- These mutations include frameshift, nonsense, and point substitutions that impair Notch receptor signaling.
- The findings establish NOTCH1/2 as the most prevalent tumor suppressors in these epithelial malignancies.
Conclusions:
- Disruption of Notch signaling and microenvironmental communication is central to SCC progression.
- The bifunctional role of Notch signaling in cancer, with context-dependent outcomes, is emphasized.
- Targeted inhibition of the Notch pathway could potentially induce squamous epithelial malignancies.
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