Mutations and mechanisms of WNT pathway tumour suppressors in cancer

A Publisher Correction to this article was published on 04 November 2020

This article has been updated

Abstract

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.

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Fig. 1: WNT signalling pathway regulation and mutation routes to WNT-independent or WNT-hypersensitive growth states in cancer.
Fig. 2: Frequencies and types of WNT pathway mutation in human cancer types.
Fig. 3: Correlation of APC truncation position and CID domain loss with tumour phenotype.
Fig. 4: Tumorigenic mechanism of AXIN1 missense mutations.
Fig. 5: RNF43 and ZNRF43 structural organization and tumorigenic mechanisms of RNF43 mutations.

Change history

  • 04 November 2020

    An amendment to this paper has been published and can be accessed via a link at the top of the paper.

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Acknowledgements

The authors thank members of the Maurice laboratory for helpful discussions and suggestions, specifically I. Jordens and A. Venhuizen for critically reading the manuscript and A. Cristobal Gonzales de Durana for providing AXIN1 immunofluorescence images. This work is part of the Oncode Institute, which is partly financed by the Dutch Cancer Society. This work was supported by European Research Council Starting Grant 242958, the Netherlands Organization for Scientific Research NWO VICI Grant 91815604 and ZonMW TOP Grant 91218050 (to M.M.M.).

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J.M.B., N.F. and M.M.M all researched data for the article, provided substantial contributions to discussions of the content and contributed equally to writing the article and to the review and/or editing of the manuscript before submission.

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Correspondence to Madelon M. Maurice.

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Glossary

Stem cell

An undifferentiated cell that divides indefinitely to renew itself and produce progenitors that differentiate into specialized cell types to replenish lost cells in the tissue during homeostasis and repair.

Missense mutations

Single base pair substitutions in the genome that result in a change in the codon, leading to the encoded protein bearing a single amino acid substitution.

Nonsense mutations

Single base pair substitutions in the genome that result in an early stop codon, leading to a prematurely truncated protein variant or nonsense-mediated mRNA decay.

Frameshift mutations

Mutations by which one or multiple base pairs are inserted in or deleted from the genome resulting in a change of the reading frame of the gene, leading to a truncated protein variant with an incorrect amino acid sequence downstream of the frameshift or nonsense-mediated mRNA decay.

Passenger mutations

Mutations that do not endow a competitive advantage but coincide with a driver mutation. Typical cancer genomes comprise 102–106 passenger mutations.

Driver mutations

Mutations that endow tumour cells with a growth or survival advantage over cells without this mutation. On average, cancer genomes comprise four or five driver mutations.

Loss-of-function (LOF) mutations

Genomic mutations resulting in an (partially) inactive gene product. They often involve loss of heterozygosity.

Promoter hypermethylation

A common mechanism of gene silencing, mediated by methylation of CpG islands in the promoter region. This mechanism is frequently misused by cancer cells to turn off the expression of (tumour suppressor) genes.

Familial adenomatous polyposis

(FAP). An autosomal dominant inherited condition that involves extensive polyp formation in the colon and a high risk of colorectal cancer, caused by a heterozygous germline mutation in adenomatous polyposis coli (APC). A second-hit mutation or loss of heterozygosity precedes malignant polyposis.

Chromosomal instability

(CIN). Genomic instability that involves frequent mis-segregation of chromosomes during cell division, resulting in gain or loss of entire chromosomes or sections of them.

Microsatellite instability

(MSI). A state of hypermutation due to impaired mismatch repair of the genome. Most common in colorectal, gastric and endometrial cancer.

Mismatch repair

(MMR). A DNA repair pathway that repairs DNA replication errors, such as base–base mismatches or erroneous insertions or deletions.

Sessile serrated adenoma

(SSA). Pre-malignant flat (or sessile) polyps predominantly observed on the right side of the colon. These polyps comprise the main precursor lesion of serrated carcinogenesis.

Left-sided CRC

(Left-sided colorectal cancer). Tumours originating distal to the splenic flexure (descending colon, sigmoid colon and rectum). Typically associated with higher levels of WNT signalling.

Right-sided CRC

(Right-sided colorectal cancer). Tumours originating proximal to the splenic flexure (caecum, ascending colon and transverse colon). Typically associated with lower levels of WNT signalling.

Loss of heterozygosity

(LOH). A frequent event in cancer, involving loss of one allele of a gene in the tumour genome, after which a single allele of the (mutated) gene remains.

Polyploid

A condition in which a cell contains more than two complete sets of chromosomes.

Hypomorphic

A mutation resulting in partial loss of function of a gene, reducing but not abolishing protein function.

Nonsense-mediated mRNA decay

(NMD). A molecular mechanism of mRNA surveillance that recognizes and eliminates mRNAs harbouring premature termination codons, thus contributing to the protection of eukaryote cells from putative toxic proteins.

Dysgeusia

Distortion of the sense of taste.

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Bugter, J.M., Fenderico, N. & Maurice, M.M. Mutations and mechanisms of WNT pathway tumour suppressors in cancer. Nat Rev Cancer (2020). https://doi.org/10.1038/s41568-020-00307-z

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