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Genetics and Genomics

TP53 mutations increase radioresistance in rhabdomyosarcoma and Ewing sarcoma

British Journal of Cancer volume 125, pages 576–581 (2021)Cite this article

Subjects

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.

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Fig. 1: CONSORT.
Fig. 2: Oncoprint.
Fig. 3: Irradiated tumour progression and survival analyses by TP53 status.

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Authors and Affiliations

  1. Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Dana L. Casey, Kenneth L. Pitter & Suzanne L. Wolden

  2. Department of Radiation Oncology, University of North Carolina School of Medicine, Chapel Hill, NC, USA

    Dana L. Casey & Gaorav P. Gupta

  3. Lineberger Comprehensive Cancer Center, University of North Carolina Hospitals, Chapel Hill, NC, USA

    Dana L. Casey & Gaorav P. Gupta

  4. Department of Pediatric Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Leonard H. Wexler & Emily K. Slotkin

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  1. Dana L. Casey
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Contributions

D.L.C., K.L.P., L.H.W., E.K.S., G.P.G. and S.L.W. designed the study. D.L.C., K.L.P., L.H.W. and S.L.W. collected the data. D.L.C., K.L.P., L.H.W., E.K.S., G.P.G. and S.L.W. contributed to the formal analysis and methodology. D.L.C., K.L.P. and S.L.W. wrote the original draft. D.L.C., K.L.P., L.H.W., E.K.S., G.P.G. and S.L.W. reviewed and edited.

Corresponding author

Correspondence to Dana L. Casey.

Ethics declarations

Ethics approval and consent to participate

Consent for genomic testing was obtained under the prospective protocol (#12–245) through the Memorial Sloan Kettering Cancer Center Institutional Review Board. Consent to participate in this retrospective analysis was waived by the Memorial Sloan Kettering Cancer Center Institutional Review Board approved protocol (#16–1125). This study was performed in accordance with the Declaration of Helsinki.

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No personal data or identifying information are being submitted.

Data availability

Data are relevant to MSKCC patients and not publicly available. We will make de-identified data available upon request after institutional approval.

Competing interests

D.L.C., K.L.P., L.H.W., E.K.S., G.P.G. and S.L.W. declare no competing interests. L.H.W. held a consultant position at EUSA Pharma in 2019, not relevant to this work.

Funding information

National Institutes of Health/National Cancer Institute Cancer Center Support Grant (P30CA008748).

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Casey, D.L., Pitter, K.L., Wexler, L.H. et al. TP53 mutations increase radioresistance in rhabdomyosarcoma and Ewing sarcoma. Br J Cancer 125, 576–581 (2021). https://doi.org/10.1038/s41416-021-01438-2

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