TP53 mutations increase radioresistance in rhabdomyosarcoma and Ewing sarcoma Journal Article


Authors: Casey, D. L.; Pitter, K. L.; Wexler, L. H.; Slotkin, E. K.; Gupta, G. P.; Wolden, S. L.
Article Title: TP53 mutations increase radioresistance in rhabdomyosarcoma and Ewing sarcoma
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. © 2021, The Author(s), under exclusive licence to Springer Nature Limited.
Journal Title: British Journal of Cancer
Volume: 125
Issue: 4
ISSN: 0007-0920
Publisher: Nature Publishing Group  
Date Published: 2021-08-17
Start Page: 576
End Page: 581
Language: English
DOI: 10.1038/s41416-021-01438-2
PUBMED: 34017087
PROVIDER: scopus
PMCID: PMC8368014
DOI/URL:
Notes: Article -- Export Date: 1 September 2021 -- Source: Scopus
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MSK Authors
  1. Suzanne L Wolden
    562 Wolden
  2. Leonard H Wexler
    192 Wexler
  3. Emily Kanaya Slotkin
    65 Slotkin
  4. Ken L Pitter
    53 Pitter
  5. Dana   Casey
    55 Casey