Mutations and mechanisms of WNT pathway tumour suppressors in cancer

Nat Rev Cancer. 2021 Jan;21(1):5-21. doi: 10.1038/s41568-020-00307-z. Epub 2020 Oct 23.


Mutation-induced activation of WNT-β-catenin signalling is a frequent driver event in human cancer. Sustained WNT-β-catenin pathway activation endows cancer cells with sustained self-renewing growth properties and is associated with therapy resistance. In healthy adult stem cells, WNT pathway activity is carefully controlled by core pathway tumour suppressors as well as negative feedback regulators. Gene inactivation experiments in mouse models unequivocally demonstrated the relevance of WNT tumour suppressor loss-of-function mutations for cancer growth. However, in human cancer, a far more complex picture has emerged in which missense or truncating mutations mediate stable expression of mutant proteins, with distinct functional and phenotypic ramifications. Herein, we review recent advances and challenges in our understanding of how different mutational subsets of WNT tumour suppressor genes link to distinct cancer types, clinical outcomes and treatment strategies.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Antineoplastic Agents / therapeutic use*
  • Humans
  • Molecular Targeted Therapy*
  • Mutation*
  • Neoplasms / drug therapy*
  • Neoplasms / genetics
  • Neoplasms / pathology
  • Tumor Suppressor Proteins / genetics*
  • Wnt Proteins / genetics*
  • Wnt Signaling Pathway / drug effects*


  • Antineoplastic Agents
  • Tumor Suppressor Proteins
  • Wnt Proteins