TP53 mutations increase radioresistance in rhabdomyosarcoma and Ewing sarcoma. Academic Article uri icon

Overview

abstract

  • BACKGROUND: p53 plays a key role in the DNA repair process and response to ionising radiation. We sought to determine the clinical phenotype of TP53 mutations and p53 pathway alterations in patients with rhabdomyosarcoma (RMS) and Ewing sarcoma (ES) treated with radiation. METHODS: Of patients with available genomic sequencing, we identified 109 patients with RMS and ES treated to a total of 286 radiation sites. We compared irradiated tumour control among tumours with TP53 mutations (n = 40) to those that were TP53 wild-type (n = 246). We additionally compared irradiated tumour control among tumours with any p53 pathway alteration (defined as tumours with TP53 mutations or TP53 wild-type tumours identified to have MDM2/4 amplification and/or CDKN2A/B deletion, n = 78) to those without such alterations (n = 208). RESULTS: The median follow-up was 26 months from radiation. TP53 mutations were associated with worse irradiated tumour control among the entire cohort (hazard ratio, HR = 2.8, P < 0.0001). Tumours with any p53 pathway alteration also had inferior irradiated tumour control (HR = 2.0, P = 0.003). On multivariable analysis, after controlling for tumour histology, intent of radiation, presence of gross disease, and biologically effective dose, TP53 mutations continued to be associated with a radioresistant phenotype (HR = 7.1, P < 0.0001). CONCLUSIONS: Our results show that TP53 mutations are associated with increased radioresistance in RMS and ES. Novel strategies to overcome this radioresistance are important for improved outcomes in p53 disruptive RMS and ES.

publication date

  • May 20, 2021

Research

keywords

  • Mutation
  • Radiation Tolerance
  • Rhabdomyosarcoma
  • Sarcoma, Ewing
  • Tumor Suppressor Protein p53

Identity

PubMed Central ID

  • PMC8368014

Scopus Document Identifier

  • 85106317570

Digital Object Identifier (DOI)

  • 10.1007/s00411-008-0188-6

PubMed ID

  • 34017087

Additional Document Info

volume

  • 125

issue

  • 4