Different hotspot p53 mutants exert distinct phenotypes and predict outcome of colorectal cancer patients.

Colorectal Neoplasms / genetics Genes, p53 Humans Mutation Phenotype Tumor Suppressor Protein p53 / genetics

Journal

Nature communications

ISSN: 2041-1723

Titre abrégé: Nat Commun

Pays: England

ID NLM: 101528555

Informations de publication

Date de publication:
19 05 2022

Historique:

received: 26 05 2021

accepted: 28 04 2022

entrez: 19 5 2022

pubmed: 20 5 2022

medline: 24 5 2022

Statut: epublish

Résumé

The TP53 gene is mutated in approximately 60% of all colorectal cancer (CRC) cases. Over 20% of all TP53-mutated CRC tumors carry missense mutations at position R175 or R273. Here we report that CRC tumors harboring R273 mutations are more prone to progress to metastatic disease, with decreased survival, than those with R175 mutations. We identify a distinct transcriptional signature orchestrated by p53R273H, implicating activation of oncogenic signaling pathways and predicting worse outcome. These features are shared also with the hotspot mutants p53R248Q and p53R248W. p53R273H selectively promotes rapid CRC cell spreading, migration, invasion and metastasis. The transcriptional output of p53R273H is associated with preferential binding to regulatory elements of R273 signature genes. Thus, different TP53 missense mutations contribute differently to cancer progression. Elucidation of the differential impact of distinct TP53 mutations on disease features may make TP53 mutational information more actionable, holding potential for better precision-based medicine.

Identifiants

DOI: 10.1038/s41467-022-30481-7 PMID: 35589715 PMC: PMC9120190

pubmed: 35589715

doi: 10.1038/s41467-022-30481-7

pii: 10.1038/s41467-022-30481-7

pmc: PMC9120190

doi:

Substances chimiques

Tumor Suppressor Protein p53 0

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

Pagination

2800

Subventions

Organisme : NCI NIH HHS

ID : P30 CA008748

Pays : United States

Informations de copyright

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