Journal
SCIENCE
Volume 367, Issue 6483, Pages 1264-+Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.aax0902
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Funding
- Canadian Institute of Health Research [CIHR 365252]
- Krembil Foundation
- HFSP [CDA00080/2015]
- Canadian Cancer Society fellowship [BC-F-16, 31919]
- Terry Fox Research Institute program grant
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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.
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