Biology Contribution
No Association Between Polygenic Risk Scores for Cancer and Development of Radiation Therapy Toxicity

https://doi.org/10.1016/j.ijrobp.2022.06.098Get rights and content
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Purpose

Our aim was to test whether updated polygenic risk scores (PRS) for susceptibility to cancer affect risk of radiation therapy toxicity.

Methods and Materials

Analyses included 9,717 patients with breast (n=3,078), prostate (n=5,748) or lung (n=891) cancer from Radiogenomics and REQUITE Consortia cohorts. Patients underwent potentially curative radiation therapy and were assessed prospectively for toxicity. Germline genotyping involved genome-wide single nucleotide polymorphism (SNP) arrays with nontyped SNPs imputed. PRS for each cancer were generated by summing literature-identified cancer susceptibility risk alleles: 352 breast, 136 prostate, and 24 lung. Weighted PRS were generated using log odds ratio (ORs) for cancer susceptibility. Standardized total average toxicity (STAT) scores at 2 and 5 years (breast, prostate) or 6 to 12 months (lung) quantified toxicity. Primary analysis tested late STAT, secondary analyses investigated acute STAT, and individual endpoints and SNPs using multivariable regression.

Results

Increasing PRS did not increase risk of late toxicity in patients with breast (OR, 1.000; 95% confidence interval [CI], 0.997-1.002), prostate (OR, 0.99; 95% CI, 0.98-1.00; weighted PRS OR, 0.93; 95% CI, 0.83-1.03), or lung (OR, 0.93; 95% CI, 0.87-1.00; weighted PRS OR, 0.68; 95% CI, 0.45-1.03) cancer. Similar results were seen for acute toxicity. Secondary analyses identified rs138944387 associated with breast pain (OR, 3.05; 95% CI, 1.86-5.01; P = 1.09 × 10–5) and rs17513613 with breast edema (OR, 0.94; 95% CI, 0.92-0.97; P = 1.08 × 10–5).

Conclusions

Patients with increased polygenic predisposition to breast, prostate, or lung cancer can safely undergo radiation therapy with no anticipated excess toxicity risk. Some individual SNPs increase the likelihood of a specific toxicity endpoint, warranting validation in independent cohorts and functional studies to elucidate biologic mechanisms.

Cited by (0)

The members of the REQUITE steering group are David Azria, Jenny Chang-Claude, Ananya Choudhury, Alison Dunning, Rebecca M. Elliott, Sara Gutiérrez-Enríquez, Tiziana Rancati, Tim Rattay, Barry S. Rosenstein, Dirk De Ruysscher, Petra Seibold, Elena Sperk, R. Paul Symonds, Hilary Stobart, Christopher J. Talbot, Ana Vega, Liv Veldeman, Adam Webb, and Catharine M. West.

This work was supported by Cancer Research UK RadNet Cambridge (C17918/A28870) and Cancer Research UK Manchester Major Centre (C147/A25254). This project was funded in part by the National Cancer Institute, National Institutes of Health K07 CA187546 (principal investigator: S.L.K), supported by Spanish Instituto de Salud Carlos III (ISCIII) funding, an initiative of the Spanish Ministry of Economy and Innovation partially supported by European Regional Development FEDER Funds (INT15/00070, INT16/00154, INT17/00133, INT20/00071; PI19/01424; PI16/00046; PI13/02030; PI10/00164), and through the Autonomous Government of Galicia (consolidation and structuring program: IN607B) (principal investigator: A.V.). RADIOGEN genotyping was carried out at CEGEN-PRB3-ISCIII; it is supported by grant PT17/0019, of the PE I+D+i 2013-2016, funded by ISCIII and ERDF. The REQUITE (principal investigator: C.M.L.W.) study received funding from the European Union's seventh Framework Programme for research, technological development, and demonstration under grant agreement No. 601826. L.F. was supported by the European Union's Horizon 2020 Research and Innovation Programme under Marie Sklodowska-Curie grant agreement No. 656144. T.R. is a National Institute of Health Research (NIHR) Academic Clinical Lecturer (CL 2017-11-002). He was previously funded by a NIHR Doctoral Research Fellowship (DRF 2014-07-079). This publication presents independent research funded by NIHR. The views expressed are those of the authors and not necessarily those of NHS, NIHR, or the UK Department of Health. C.M.L.W. (principal investigator of RAPPER) is supported by the NIHR Manchester Biomedical Research Centre. RAPPER was supported by Cancer Research UK grants C1094/A18504, C147/A25254, and C147/A25254. The PRACTICAL consortium was supported by Cancer Research UK grants C5047/A7357, C1287/A10118, C1287/A16563, C5047/A3354, C5047/A10692, and C16913/A6135.

Disclosures: none.

Data sharing statement: Research data are stored in institutional repositories and may be shared upon request to the corresponding author.

© 2022 The Authors. Published by Elsevier Inc.