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No association between polygenic risk scores for cancer and development of radiotherapy toxicity
Barnett, G. C. Kerns, S. L. Dorling, L. Fachal, L. Aguado-Barrera, M. E. Martínez-Calvo, L. Jandu, H. K. Welsh, C. Tyrer, J. Coles, C. E.
Barnett, G. C.
Kerns, S. L.
Dorling, L.
Fachal, L.
Aguado-Barrera, M. E.
Martínez-Calvo, L.
Jandu, H. K.
Welsh, C.
Tyrer, J.
Coles, C. E.
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Abstract
Purpose: To test whether updated polygenic risk scores (PRS) for susceptibility to cancer affect risk of radiotherapy toxicity.
Experimental design: Analyses included 9,717 patients with breast (n=3,078), prostate (n=5,748) or lung (n=891) cancer from XXXX and XXXX Consortia cohorts. Patients underwent potentially curative radiotherapy and were assessed prospectively for toxicity. Germline genotyping involved genome-wide single nucleotide polymorphism (SNP) arrays with non-typed SNPs imputed. PRS for each cancer were generated by summing literature-identified cancer susceptibility risk alleles: 352 breast, 136 prostate, 24 lung. Weighted PRS were generated using log odds ratios 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%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 oedema (OR=0.94; 95%CI 0.92- 0.97; P=1.08 × 1 0-5).
Conclusions: Patients with increased polygenic predisposition to breast, prostate or lung cancer can safely undergo radiotherapy with no anticipated excess toxicity risk. Some individual SNPs increase likelihood of a specific toxicity endpoint warranting validation in independent cohorts and functional studies to elucidate biologic mechanisms.
Authors
Barnett, G. C.
Kerns, S. L.
Dorling, L.
Fachal, L.
Aguado-Barrera, M. E.
Martínez-Calvo, L.
Jandu, H. K.
Welsh, C.
Tyrer, J.
Coles, C. E.
Haviland, J. S.
Parker, C.
Gómez-Caamaño, A.
Calvo-Crespo, P.
Sosa-Fajardo, P.
Burnet, Neil G
Summersgill, Holly
Webb, A.
De Ruysscher, D.
Seibold, P.
Chang-Claude, J.
Talbot, C. J.
Rattay, T.
Parliament, M.
De Ruyck, K.
Rosenstein, B. S.
Pharoah, P. D. P.
Dunning, A. M.
Vega, A.
West, Catharine M L
Kerns, S. L.
Dorling, L.
Fachal, L.
Aguado-Barrera, M. E.
Martínez-Calvo, L.
Jandu, H. K.
Welsh, C.
Tyrer, J.
Coles, C. E.
Haviland, J. S.
Parker, C.
Gómez-Caamaño, A.
Calvo-Crespo, P.
Sosa-Fajardo, P.
Burnet, Neil G
Summersgill, Holly
Webb, A.
De Ruysscher, D.
Seibold, P.
Chang-Claude, J.
Talbot, C. J.
Rattay, T.
Parliament, M.
De Ruyck, K.
Rosenstein, B. S.
Pharoah, P. D. P.
Dunning, A. M.
Vega, A.
West, Catharine M L
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Date
2022
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Article
Citation
Barnett GC, Kerns SL, Dorling L, Fachal L, Aguado-Barrera ME, Martínez-Calvo L, et al. No association between polygenic risk scores for cancer and development of radiotherapy toxicity. International journal of radiation oncology, biology, physics. 2022 Jul 12. PubMed PMID: 35840111. Epub 2022/07/16. eng.