Cdkn2a Suppresses Metastasis in Squamous Cell Carcinomas Induced by the Gain-Of-Function Mutant p53(R172H)

J Pathol. 2016 Oct;240(2):224-34. doi: 10.1002/path.4770.

Abstract

p53 (TP53) is the most frequently mutated gene in squamous cell carcinomas (SCCs) of the skin and head and neck. Certain p53 mutations are oncogenic and promote invasion and metastasis in SCCs. However, it is unclear how the oncogenic function of mutant p53 is modulated by other molecular alterations that co-exist in SCCs. Here, we show that deletion of the p53 gene and activation of an endogenous p53(R172H) gain-of-function mutation in the skin induce carcinomas with similar kinetics and penetrance. Deletion of p53 induced primarily well-differentiated SCCs. However, most of the tumours induced by p53(R172H) were poorly differentiated SCCs, the only metastatic tumours in this model. These tumours expressed higher levels of cyclin D1 than the well-differentiated SCCs and spindle carcinomas that developed in these mice. Unexpectedly, metastasis was not observed in mice that developed spindle carcinomas, which expressed high levels of the tumour suppressors p16(Ink4a) and p19(Arf) , encoded by Cdkn2a, a gene frequently deleted in human SCCs. Remarkably, deletion of the Cdkn2a gene in p53(R172H) -induced SCCs promoted a dramatic increase in metastasis rates and a shorter survival in mice that developed these tumours, compared with those observed in mice with tumours in which Cdkn2a was deleted in the presence of a p53 loss-of-function mutation or wild-type p53. Accordingly, the survival of patients with head and neck SCCs bearing co-occurring high-risk p53 mutations and CDKN2A homozygous deletions was much shorter than that of patients with tumours in which high-risk p53 mutations did not contain CDKN2A homozygous deletions, or that of patients with tumours in which homozygous CDKN2A deletions co-existed with either low-risk p53 mutations or potential loss-of-function mutations in p53. These findings genetically identify a population of SCC patients with worst outcomes and will help to predict outcomes according to the p53 status and alterations in CDKN2A. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Keywords: Cdkn2a; metastasis; p53; squamous cell carcinoma.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Carcinoma, Squamous Cell / genetics*
  • Carcinoma, Squamous Cell / metabolism
  • Carcinoma, Squamous Cell / mortality
  • Carcinoma, Squamous Cell / pathology
  • Cyclin-Dependent Kinase Inhibitor p16 / genetics*
  • Cyclin-Dependent Kinase Inhibitor p16 / metabolism
  • Databases, Genetic
  • Gene Deletion
  • Head and Neck Neoplasms / genetics
  • Head and Neck Neoplasms / metabolism
  • Head and Neck Neoplasms / mortality
  • Head and Neck Neoplasms / pathology
  • Humans
  • Mice
  • Mutation*
  • Neoplasm Metastasis / genetics*
  • Neoplasm Metastasis / pathology
  • Survival Rate
  • Tumor Suppressor Protein p53 / genetics*
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • Cyclin-Dependent Kinase Inhibitor p16
  • Tumor Suppressor Protein p53