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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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.
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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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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.
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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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DOI: https://doi.org/10.1038/s41416-021-01438-2
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