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Rare driver mutations in head and neck squamous cell carcinomas converge on NOTCH signaling.
- Source :
-
Science (New York, N.Y.) [Science] 2020 Mar 13; Vol. 367 (6483), pp. 1264-1269. - Publication Year :
- 2020
-
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.<br /> (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)
- Subjects :
- ADAM10 Protein genetics
Amyloid Precursor Protein Secretases genetics
Animals
CRISPR-Cas Systems
Female
Genetic Testing
HEK293 Cells
Humans
LIM Domain Proteins genetics
Male
Membrane Proteins genetics
Mice
Mice, Inbred C57BL
Mice, Mutant Strains
Mutation
Receptors, Notch genetics
Signal Transduction genetics
Genes, Tumor Suppressor
Genetic Predisposition to Disease
Head and Neck Neoplasms genetics
Squamous Cell Carcinoma of Head and Neck genetics
Tumor Suppressor Proteins genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1095-9203
- Volume :
- 367
- Issue :
- 6483
- Database :
- MEDLINE
- Journal :
- Science (New York, N.Y.)
- Publication Type :
- Academic Journal
- Accession number :
- 32165588
- Full Text :
- https://doi.org/10.1126/science.aax0902