Rare driver mutations in head and neck squamous cell carcinomas converge on NOTCH signaling

Science. 2020 Mar 13;367(6483):1264-1269. doi: 10.1126/science.aax0902.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADAM10 Protein / genetics
  • Amyloid Precursor Protein Secretases / genetics
  • Animals
  • CRISPR-Cas Systems
  • Female
  • Genes, Tumor Suppressor*
  • Genetic Predisposition to Disease*
  • Genetic Testing
  • HEK293 Cells
  • Head and Neck Neoplasms / genetics*
  • Humans
  • LIM Domain Proteins / genetics
  • Male
  • Membrane Proteins / genetics
  • Mice
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Mutation
  • Receptors, Notch / genetics
  • Signal Transduction / genetics
  • Squamous Cell Carcinoma of Head and Neck / genetics*
  • Tumor Suppressor Proteins / genetics*


  • AJUBA protein, human
  • LIM Domain Proteins
  • Membrane Proteins
  • Receptors, Notch
  • Tumor Suppressor Proteins
  • Amyloid Precursor Protein Secretases
  • ADAM10 Protein
  • ADAM10 protein, human