Rare driver mutations in head and neck squamous cell carcinomas converge on NOTCH signaling
- 13 March 2020
- journal article
- research article
- Published by American Association for the Advancement of Science (AAAS) in Science
- Vol. 367 (6483), 1264-1269
- https://doi.org/10.1126/science.aax0902
Abstract
In most human cancers, only a few genes are mutated at high frequencies; most are mutated at low frequencies. The functional consequences of these recurrent but infrequent “long tail” mutations are often unknown. We focused on 484 long tail genes in head and neck squamous cell carcinoma (HNSCC) and used in vivo CRISPR to screen for genes that, upon mutation, trigger tumor development in mice. Of the 15 tumor-suppressor genes identified, ADAM10 and AJUBA suppressed HNSCC in a haploinsufficient manner by promoting NOTCH receptor signaling. ADAM10 and AJUBA mutations or monoallelic loss occur in 28% of human HNSCC cases and are mutually exclusive with NOTCH receptor mutations. Our results show that oncogenic mutations in 67% of human HNSCC cases converge onto the NOTCH signaling pathway, making NOTCH inactivation a hallmark of HNSCC.Keywords
Funding Information
- Human Frontier Science Program (CDA00080/2015)
- Canadian Institutes of Health Research (365252)
- Canadian Breast Cancer Foundation (BC-F-16#31919)
- Canada Research Chairs
- Krembil Foundation (N/A)
- Terry Fox Research Institute (Terry Fox Research Institute Program Grant)
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