Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 108, Issue 43, Pages 17761-17766Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1114669108
Keywords
cancer genetics; genomic; cellular signaling
Categories
Funding
- Leukemia and Lymphoma Society
- National Institutes of Health (NIH) [P01 CA119070, R01 CA092433]
- European Research Council
- Cancer Research-UK
- Department of Energy [DE-AC02-05CH11231]
- NIH/National Cancer Institute (NCI) [P50 CA 58207, U54 CA 112970]
- National Human Genome Research Institute [U24 CA 126551]
- US Army Medical Research Acquisition Activity [W81XWH-07-1-0663]
- Stand Up To Cancer-American Association for Cancer Research Dream Team [SU2C-AACR-DT0409]
- University of California
- Dickson Emeritus Professorship
- NIH/NCI [U24 CA1437991, KO8 CA137153]
- Yale SPORE in Skin Cancer
- National Cancer Institute [P50 CA121974]
- NIH [AR051930, R01AG028492]
- Department of Veterans Affairs Medical Research Service
- NIH/National Institute of Arthritis and Musculoskeletal and Skin Diseases [5KO8AR057763]
- Samsung Advanced Institute of Technology
- Dermatology Foundation
- Cancer Research UK [13044] Funding Source: researchfish
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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 similar to 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.
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