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A pan-cancer analysis reveals nonstop extension mutations causing SMAD4 tumour suppressor degradation

Sonam Dhamija1,2, Chul Min Yang1, Jeanette Seiler2

  • 1Division of Cancer Research, Department of Thoracic Surgery, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, German Cancer Consortium (DKTK) Partner Site Freiburg, Freiburg, Germany.

Nature Cell Biology
|July 29, 2020
PubMed

Insights

Nonstop mutations, previously found in hereditary diseases, are now identified as functionally important in cancer genetics. These mutations lead to the loss-of-function of tumor suppressors like SMAD4.

Area of Science:

  • Genetics
  • Molecular Biology
  • Cancer Research

Background:

  • Nonstop mutations alter gene expression by changing stop codons to sense codons, leading to protein extensions.
  • While known in hereditary diseases, the role of nonstop mutations in cancer genetics remained largely unexplored.

Purpose of the Study:

  • To investigate the prevalence and functional impact of nonstop mutations across various cancer types.
  • To establish a comprehensive database of nonstop mutations in cancer.

Main Methods:

  • A pan-cancer analysis was conducted, curating and analyzing 3,412 nonstop mutations from 62 tumor entities.
  • The study generated a comprehensive database (http://NonStopDB.dkfz.de) for public access.

Main Results:

  • Six distinct nonstop extension mutations were identified in the tumor suppressor SMAD4, resulting in a 40-amino acid extension of its carboxy terminus.
  • These SMAD4 extensions triggered rapid degradation of the mutant proteins via the ubiquitin-proteasome system.
  • A specific 10-amino acid hydrophobic degron sequence within the extension was crucial for complete SMAD4 protein loss.

Conclusions:

  • Nonstop mutations can play a significant role in cancer development.
  • These mutations contribute to a loss-of-function mechanism for tumor suppressors, exemplified by SMAD4.
  • The findings highlight a novel mechanism of tumor suppressor inactivation in cancer genetics.

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